Behavioural, hormonal and neurobiological mechanisms of aggressive behaviour in human and nonhuman primates.

Physiology & Behavior 143 (2015) 121–135

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Physiology & Behavior journal homepage: www.elsevier.com/locate/phb

Review

Behavioural, hormonal and neurobiological mechanisms of aggressive behaviour in human and nonhuman primates Rosa Maria Martins de Almeida ⁎, João Carlos Centurion Cabral, Rodrigo Narvaes Institute of Psychology, Laboratory of Experimental Psychology, Neuroscience and Behaviour, Federal University of Rio Grande do Sul (UFRGS), 2600 Ramiro Barcelos St, Porto Alegre 90035-003, Brazil

H I G H L I G H T S • • • • •

Sex plays an essential role in agonistic behaviours in human and nonhuman primates. Testosterone, progesterone, cortisol and vasopressin affect sex-specific aggression. Neurotransmitters, mainly GABA and 5-HT, are crucial for sex-specific aggression. Positive allosteric modulator of GABAA-R influences sexually dimorphic aggression. Neurotransmitter, neuromodulator and hormone relations are the future direction of the field.

a r t i c l e

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Article history: Received 6 December 2014 Received in revised form 25 February 2015 Accepted 28 February 2015 Available online 3 March 2015

Aggression is a key component for social behaviour and can have an adaptive value or deleterious consequences. Here, we review the role of sex-related differences in aggressive behaviour in both human and nonhuman primates. First, we address aggression in primates, which varies deeply between species, both in intensity and in display, ranging from animals that are very aggressive, such as chimpanzees, to the nonaggressive bonobos. Aggression also influences the hierarchical structure of gorillas and chimpanzees, and is used as the main tool for dealing with other groups. With regard to human aggression, it can be considered a relevant adaptation for survival or can have negative impacts on social interaction for both sexes. Gender plays a critical role in aggressive and competitive behaviours, which are determined by a cascade of physiological changes, including GABAergic and serotonergic systems, and sex neurosteroids. The understanding of the neurobiological bases and behavioural determinants of different types of aggression is fundamental for minimising these negative impacts. © 2015 Elsevier Inc. All rights reserved.

Keywords: Aggression Agonistic behaviour Sex steroids Cortisol Serotonin neurotransmitter GABA neurotransmitter

Contents 1. 2.

Introduction . . . . . . . . . . . . Aggression in nonhuman primates . 2.1. Species differences . . . . . 2.2. Sex differences . . . . . . . 2.3. Perspectives . . . . . . . . 3. Human aggression . . . . . . . . . 3.1. Types of aggressive behaviour 3.2. Peripheral hormones . . . . 3.3. Neurobiological mechanisms . 3.4. Genetic bases . . . . . . . . 3.5. Perspectives . . . . . . . . 4. Conclusions . . . . . . . . . . . . References . . . . . . . . . . . . . . .

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⁎ Corresponding author at: Institute of Psychology, Federal University of Rio Grande do Sul, 2600 Ramiro Barcelos St, Porto Alegre, 90035-003 Rio Grande do Sul, Brazil. E-mail addresses: [email protected], [email protected] (R.M.M. de Almeida), [email protected] (J.C.C. Cabral), [email protected] (R. Narvaes).

http://dx.doi.org/10.1016/j.physbeh.2015.02.053 0031-9384/© 2015 Elsevier Inc. All rights reserved.

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R.M.M. de Almeida et al. / Physiology & Behavior 143 (2015) 121–135

1. Introduction Aggression is an individual or collective social behaviour that has a highly adaptive value [1,2]. It may be defined in general terms as a hostile behaviour with the intention of inflicting damage or harm [3]. The display of agonistic behaviour has evolved in the context of defending or obtaining resources for almost all species of primates and other presocial mammals [4–7]. However, among humans, aggression and violent crimes are considered one of the most serious urban problems currently faced [8,9]. The remarkable sex differences in aggressive behaviour in primates may be explained by natural determinants. The knowledge on biological and behavioural aspects of this significant sexual dimorphism is essential to be able to not only manage and predict more accurately the social consequences of aggression, but also for guidance of public and judicial policies. Hence, ethological analyses have helped to elucidate the differences and similarities between human and nonhuman primates, as well as the phylogenetic origins of social behaviours. The comparative behavioural sciences have indicated that primates, especially those belonging to the Hominidae family, present a significant sexually dimorphic pattern of aggressive behaviour [10]. These data, along with physiological analyses, may clarify the role of sex and gender on aggressive behaviour. Nevertheless, the interdisciplinary nature of the field, and the wide and continuous effort of the scientific community to deepen understanding of aggressive behaviour, make the task of synthesising these data a major challenge, which must constantly be overcome. Here, we propose the integration of the behavioural, hormonal and neural bases of sex differences in aggressive behaviour in both human and nonhuman primates, along with future directions for aggression research. 2. Aggression in nonhuman primates Aggressive behaviour is well known as a key element of primate social behaviour [6]. There are some main contexts in which aggression is important in primates, e.g. intergroup resource defence, antipredator behaviour, predation, and intragroup social contexts such as dominance contests (for food, mates, status etc.) and reproduction [11]. However, primates also show pathological self-directed aggression as selfinjurious behaviour [11]. Displays of aggression are common in all species of primates, and male–male competition associated with physical aggression is prevalent in all great apes [12]. 2.1. Species differences It is important to differentiate the great apes from the other primates due to evolutionary differences of the first that might favour aggressive behaviour — for example, short legs might not only be associated with better climbing, but also with better stability and stronger impulses in a fight [13]. Moreover, there are many different social structures among primates. For example, while chimpanzees (Pan troglodytes) and bonobos (Pan paniscus) usually live in large groups [14], male orangutans (Pongo pygmaeus) are extremely intolerant of each other [15]. Similarly, most encounters involving male gorillas result in displays of aggression. Among the groups of chimpanzees, aggressive encounters are frequent, but the tension inside the group is usually mended by the reconciliatory behaviour these animals show [14]. Whereas intragroup aggression is stressful, intergroup aggression poses a much bigger threat to chimpanzees than social stress from hierarchical ranks. Chimpanzees are known to attack and kill males in other groups to expand their territories [16,17]. Nonlethal intergroup fights are widespread in primates, but the pattern of killing males in other groups is, to this point, recorded only in humans and chimpanzees [17]. These lethal attacks usually happen when the risk of physical harm is minimal to the aggressors and where the balance of power between the groups is extremely asymmetrical. Wrangham and colleagues [18] calculated the median risk of violent death in chimpanzees

due to intergroup violence and found that it ranges from 69 to 287 per 100,000 per year, and the victims were mostly adult males (42.4%) and infants (51.5%). Watts and colleagues [19] report that, while the injuries on the aggressors were minimal, the attacked males were reported to have broken bones, wounds covering a considerable part of the exposed surfaces of the victim, castration and torn thoraxes, despite resisting intensely [20]. More astonishingly, chimpanzees can also attack humans for various reasons [21]; these attacks may be due to food deprivation or surprise encounters between humans and chimpanzees in areas of common use, such as paths. Most of these attacks were predatory, having children as the main targets of the primates. The children were between 18 months and 12 years old, and 7 out of 10 attacks happened when the children were alone; one happened when a man was present, but the man had a physical disability. However, once they were pursued by a human, the attacking chimpanzees would immediately cease the attack. While the occurrences were rare, Hockings and colleagues [21] reported that chimpanzees have demonstrated bold behaviour by moving up to 182 m away from the edge of the forest to capture human prey; and, on two occasions, a baby was removed from the doorway of a house. Unlike chimpanzees, bonobos show extremely low levels of intragroup aggressive behaviour. Even between groups, they rarely engage in physical aggression, which their phenotype reflects. They have much smaller canines when compared to their body sizes than those of chimpanzees and gorillas, and they rarely obtain bone fractures from interspecific confrontation [13]. There are no known cases of male–female aggression in bonobos, since females show feeding priority over males; contrarily from what happens with chimpanzees, the females always occupy higher ranks in the bonobo hierarchy [22]. Hare and colleagues [22] proposed that this strong reduction in the expression of the aggressive behaviour in bonobos is due to a natural domestication process that occurred in the species, describing many phenotypical traits that bonobos share when compared to other domesticated animals that have a “wild counterpart” (i.e., dogs and wolves), such as reduced cranial size and diminished sexual dimorphism in the brains and crania when compared to chimpanzees. While chimpanzees and bonobos usually live in large groups, gorillas' groups are much smaller (sometimes even living as lone males) and have periods of sub- and super-grouping. Lowland, sometimes called western, gorillas (Gorilla gorilla gorilla) are more frugivorous and use larger home ranges than the closely-related mountain gorilla (Gorilla beringei beringei) [23]. Lowland gorillas are also more tolerant than mountain gorillas to adult males in other groups, even though it is unusual to have more than one silverback (adult males). In a study on home-ranges of lowland gorillas, Bermejo [23] found that 50% of the encounters between his focal group of gorillas and lone males resulted in avoidance, while the other 50% involved aggressive displays. However, encounters between his focal groups and other groups showed different results: 64% of the time, the focal group showed tolerance, and 14% of the time, the focal group avoided the other groups. The aggressive encounters corresponded to approximately 21%, with 7% involving physical aggression. Therefore, only a small portion of the encounters resulted in aggression, and the silverback gorilla of the focal group sometimes tolerated other males to the point where they conested, showing a much different behaviour than the more aggressive mountain gorilla [23]. Mountain gorillas form groups that contain one or more silverbacks [24], and approximately 40% of the mountain gorilla groups contain more than one male; however, one single male is likely to monopolise the reproduction in his group, which is similar to what happens in the lowland gorilla. Mountain gorillas are not only much less tolerant than lowland gorillas to males in other groups [23], but they also perform aggressive displays to females [25]. Interestingly, the silverbacks from lowland gorilla groups also control the aggression between the younger members of the group by physically intervening in conflicts [26], especially in captive groups, where resources, such as


food and space, are not limited. In fact, conciliatory behaviour has already been observed in lowland gorillas [27]. Aggression is a very demanding behaviour and has great risks, both physically and socially. Therefore, the conciliatory behaviour known as policing is a way of “mending the damages” caused by aggressive behaviour inside groups. By definition, policing is the impartial monitoring and attempted control of conflict among group members that is performed by third parties [28]. Primates show many ways to conciliate the “brawlers” after aggressive displays or confrontations, and de Waal [14] has shown that animals that were experimentally induced to fight, but were then allowed to reconciliate, expressed much more tolerance to each other than animals that had been prevented from reconciliating. Other members of the group may also intervene, with females being the most frequent “catalyst”. Something similar happens in multimale mountain gorilla groups, as the females, subordinate males and juveniles intervene in order to prevent two silverbacks from fighting. Captive orangutans frequently engage in aggressive confrontations and third-party interventions have also been observed [29]. Rhesus monkeys (Macaca mulatta) also show policing, as described by Beisner and McCowan [28]. Earlier, McCowan and colleagues [30] analysed the conflict dynamics of rhesus monkeys and they observed that the behaviour of intervening in a fight is an effective way to avoid harsh consequences to the group due to the aggression between its members; nonetheless, it also bears a great risk to the intervener. However, unlike what happens with mountain gorillas, the individuals that were found to be the key interveners were the ones with higher social ranks, and most of the time (75%), were males. Stress is another major factor that influences social interactions in primates. The hierarchical structure and intergroup fights of apes are sources of stress, and there are clear differences in how stress affects animals in a social hierarchy. In some species, the subordinate animals show higher levels of stress; in contrast, there are others, like the chimpanzees, in which the higher ranked animals are more stressed than those in the lower ranks [31]. Captive rhesus monkeys and feral baboon groups also show higher stress in high-ranked individuals, but for different reasons than chimpanzees. While chimpanzees have to assert their dominance physically and constantly, captive rhesus macaques and feral baboons have periods of high social instability, which threatens the dominant males. Conversely, a considerable part of these studies was performed with captive animals. It is worth noting that the ethology of aggression in nonhuman primates and its neuroscience are hard to conciliate, since there are many behavioural differences in captive and wild animals. For instance, both cortisol and testosterone not only show high inter-individual differences, but are also influenced by the circadian rhythm and environmental factors. Generally, elevated stress affects cortisol secretion, which is known to have an impact on aggression when associated with high levels of testosterone. Cortisol and testosterone are produced by two antagonical axes: the hypothalamic–pituitary–adrenal (HPA) and the hypothalamic– pituitary–gonadal (HPG), respectively, which inhibit each other at different levels creating a complex mechanism that regulates aggressive behaviour in males [32]. Cortisol in particular is associated with the duration of stress; while acute stress can lead to higher cortisol levels, animals subjected to chronic stress may not show alterations in the levels of the hormone [11]. In captive chimpanzees, Yamanashi and colleagues [33] found a significant and positive correlation between the number of aggressions received and hair cortisol concentrations. On the other hand, in females of many species of callitrichids, the cortisol levels appear not to be associated with stress; instead, the main increase might be related to endocrine status and reproductive events [34]. Wild common marmosets showed elevated cortisol levels during late pregnancy [35]. The rise in cortisol levels during late pregnancy was also seen in a study with captive common marmosets; however, a direct comparison of mothers (who have a dominant status) and daughters (who are subordinates) showed no difference in cortisol levels of the two different social statuses [36]. In a study with a non-callitrichid primate, the ring-

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tailed lemur, the top ranking females showed higher faecal glucocorticoid (GC) levels than the low females in their groups, and the GC levels were also related to aggressive initiation — the groups and individuals with higher GC levels were also the ones that usually initiated aggression [37]. Testosterone is considered one of the main molecules in the regulation of aggressive behaviour and dominance, and it is the final product of the HPG axis [7,38]. For example, there are changes in the activity of the HPG axis in olive baboons (Papio anubis) that are dominant or subordinate males in the social hierarchy; while dominant males have much higher testosterone levels, subordinate males have decreases in the basal levels [39]. However, these differences are not always evident; they become apparent when animals are challenged with an acute stressor. The mating season is a particularly challenging period in which males compete with each other for access to sexually receptive females. The “Challenge Hypothesis” proposes that testosterone is involved in the mediation of aggression in periods of heightened conflict between males [40]. To cope with the increased physical and energetic demands, males undergo raises in both testosterone (according to the Challenge Hypothesis) and cortisol (the “energy mobilization hypothesis”, as proposed by Romero [41]) levels [42]. The reproductive patterns are, therefore, extremely relevant to understand how aggressive behaviour works in primates. Seasonal breeders, such as the chimpanzees and the long-tailed macaques (Macaca fuscata) have to cope with one particular period of time with higher threats and higher rewards for aggression [42]. On the other hand, mantled howler monkeys (Alouatta palliata) and other nonseasonal breeders do not suffer from stress spikes throughout the year; rather, their testosterone and cortisol levels are associated with presence of other groups or solitary males [42]. In ring-tailed lemurs (Lemur catta), the faecal testosterone levels are more closely associated with aggression during the mating season, when social challenges are frequent, than during the most stable period that precedes mating; besides, faecal testosterone and aggression rate are correlated in the days of and the day after estrus, but not in the two days that preceded it. Along with the data from olive baboons, these findings reinforced the importance of the “Challenge Hypothesis” as a relevant phenomenon in the behaviour of nonhuman primates [43]. Mantled howler monkeys show much lower rates of aggression than lemurs, rhesus monkeys and chimpanzees [44], but studies with this species also corroborate the Challenge Hypothesis. Cristóbal-Azkarate and colleagues [44] collected faeces from free-ranging resident males to measure testosterone levels in relation to the number and density of solitary males. Interestingly, the testosterone levels of resident males were higher independently of their rank, and the levels were associated with the number and density of solitary males. These findings suggest that the appearance of new male in the group had the potential to negatively affect the reproductive success of all males. Testosterone is rather associated with competitive behaviours and dominance than aggression [7]. A study conducted by Steklis and colleagues [45] with vervet monkeys (Cercopithecus aethiops sabaeus) shows that not only the dominant males with higher serum testosterone levels were also the ones who initiated aggressive encounters, but also that the number of encounters won was highly associated with both aggressive initiation and overall aggression. This phenomenon is known as the “winning effect”, in which individuals experiencing a reward from its overt aggressive behaviour tend to increase their rates of agonistic behaviour [45]. Surprisingly, this study also discussed the idea that testosterone is not directly associated with dominance; rather, it is associated with the expression of aggressive behaviour in dominant males. Measures of faecal androgens levels in wild male golden lion tamarins (Leontopithecus rosalia) have shown a much different context than in other callitrichids. Since golden lion tamarins are cooperative breeders, subordinate males that are related to the dominant ones do not show lower levels of faecal androgens, but the cortisol levels of

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the subordinate males were not significantly different from those of the dominant ones. Another intriguing finding regarding cortisol levels was that it tends to drop in individual males when another male moved out of the natal group and into a breeding position [46]. Therefore, even though there is a social hierarchy in the golden lion tamarin males, it is not particularly stressful to neither the dominant and subordinate males. Housing conditions in captive primates are also a factor that regulates aggressive behaviour. Animals subjected to poor conditions during captivity have shown abnormal aggression, including self-injuring behaviour [47]. Even though pairing is a way to keep the animal healthier, sometimes the pairing attempts of animals that were kept in single cages can result in displays of aggression that might lead to severe wounds or even death of one of the animals, among other dysfunctional behaviours [48]. The self-injurious behaviour is a signal of stress, and it is very hard to stop or revert once it starts [49]. However, Weed and colleagues [50] used socialisation as a treatment for this dysfunctional behaviour in a rhesus monkey, since neither environmental enrichment nor changes to the physical environment proved to be effective. 2.2. Sex differences Aggression is a much more common phenomenon in males than it is in females due to stronger intrasexual competition and higher payoffs of escalated aggression [51]. However, reproductive success is also important for females, as well as greater access to resources, and females can also show intense aggression. Female common marmosets (Callithrix jacchus) were reported to kill other females' infants [52], and female chimpanzees have been reported to intensely attack immigrant females and even steal or kill other females' babies [51]. Female chimpanzees leave their natal groups when they reach sexual maturity, and even though female–female aggression is a rare event, the immigrants are regularly attacked by the local females [53]. Even though female aggression directed towards males is much less common in species were the higher-ranked individuals are males, there are reports of such phenomenon. One particular study carried out by Setchell and colleagues [54] describes a very violent cooperative attack of the females in a semi-free ranging of mandrills (Mandrillus sphinx) towards the alpha of the group after he was injured in a fight against another male. This data shows that even though males dominate the group and assume a higher-rank position, females can still interfere on the hierarchy of the group by actively excluding, and even killing, unwanted males from the group. Additionally, not only the majority of the group did not interfere in the attack, but also when one of the males tried to intervene, the females chased him away. Females also have a hierarchical structure that affects their food access, and, therefore, their offspring survivability [55]. This has been reported in several different research sites, such as Gombe, Kanyawara, Mahale and Tai [55], but in each place, high-ranking females had different advantages. In Tai, females associate at high levels, and high-ranking females win more contests over food items; in Kanyawara, the highranked females have access to the crowns of the trees, where the best fruits are located. High-ranking females also have preferential access to areas with higher food productivity and can inhibit their use by submissive females. Finally, they are more efficient at defending highquality core areas. Kahlenberg and colleagues [53] evaluated the hypothesis that females do not contest for access to shared food patches; rather, they compete to occupy the parts of the home range that facilitate longterm access to preferred food sources. Their results showed that highranked females indeed occupied better neighbourhoods than lowerranked females and that rank increased with age. As a result, even though females are not physically aggressive, they are very competitive, and competition has a significant influence on the reproductive success of females. They will, however, use physical aggression against immigrant females. Immigrant females receive significantly more aggression

than natal females of the same age, probably because natal females will emigrate from the group when they reach sexual maturity and, therefore, are not long-term competitors to the local females. Since chimpanzee females emigrate from their natal groups and are targets of physical aggression when entering new groups, it is not unreasonable to wonder how this particular reproductive strategy evolved as the main behaviour for females. The answer to this puzzling question lies in male protection of immigrant females. When a female reaches sexual maturity, their genitals swell, which signals to males that they are sexually available. While females from other communities are often attacked by males from different communities [56], immigrant females are protected from the resident ones by males, creating a conflict of interest between resident females, who suffer from increased competition, and resident males who benefit from increased mating opportunities [57]. Rhesus monkeys are the most despotic of the macaques, showing interactions of highly asymmetrical dominance even in the wild, and are naturally aggressive [58], showing even higher levels of aggression in captivity. High-ranking females are more likely to be involved in mild aggression to assert their dominance. However, intense aggression does not seem to play this role, as high-ranking females were not more involved in cases of severe aggression than the low-ranking females [58]. Interestingly, both male and female macaques showed lower levels of aggression when the enclosures had grass cover instead of gravel, even during the breeding season. Since rhesus macaques are very aggressive in the wild, and the physical limitation of space in captivity exacerbates this behaviour, changing the ground cover of the enclosure might be a simple way to reduce the potential damage caused by aggressive outbursts to the communities of captive rhesus. High ranked rhesus macaques females show differences in the serotonergic function when compared to low ranking females [59]. Females with higher ranks exhibited higher levels of serotonin metabolite, 5hydroxy-indoleic acid (5-HIAA), in the cerebrospinal fluid (CSF) than lower ranking females, and CSF baselines could be used to predict the acquisition of social rank. The concentrations also demonstrated to be stable over time, even in stressful conditions. These results suggest that adult females show a stable, individual predisposition in the response of CNS serotonin (5-HT) and catecholamines. The effects of estradiol (E2), the primary hormone related to sexual traits in females, on serum oxytocin, which largely influences pair bonding, maternal care and other social behaviours [60], in females are modified by their social status and by polymorphisms in the serotonin transporter genes [61]. E2's role in the regulation of social behaviours is, in part, likely related to its modulation of 5-HT neural system by increasing 5-HT synthesis and modulating 5-HT reuptake transporter [61]. This is similar to what happens in males, where testosterone is related to the serotonergic metabolism [62] and acts in the orbitofrontal region of the prefrontal cortex, reducing the mRNA levels of the serotonin receptors and the serotonin turnover in the medial prefrontal cortex [63]. These findings regarding the role of both serotonin and estradiol align with what is found in humans. 2.3. Perspectives The ethological work with aggression in nonhuman primates can help us understand the behaviour of our ancestors, our neurological foundations to develop aggressive behaviour and the strategies that the human species developed to cope with aggression in large groups. While chimpanzees and bonobos are well studied, searching the keywords “orangutan AND aggression” in three highly renowned databases will yield thirteen results on Scopus, nine results on PubMed and eleven results on Web of Science, showing the scarcity of studies in the area. There are many dangers of working with apes, specifically with highly aggressive ones such as orangutans, but it is worth noting that knowledge of how orangutans behave in the wild has a major impact on how they have to be treated in captivity. Orangutans are also


“endangered” according to the IUCN red list on their website (www. iucnredlist.org), which increases the urgency of ethological studies with this species. There are many limitations to these works, but they should not be seen as impediments; rather, they are opportunities to develop new methodologies that assess, both directly and indirectly, the levels of neurotransmitters and their influences on the mechanisms underlying aggressive behaviour. Neurological research on primates, albeit hard to conduct due to behavioural and ethical reasons, is of major importance to understanding the evolution of human aggression on a neural basis. 3. Human aggression Human aggression is a heterogeneous behaviour, influenced by several environmental and biological factors. These factors can have adaptive benefits or negative impacts as well as anti-social characteristics [2, 64,65]. Aggressive behaviours are associated with adjustment problems and several psychopathological symptoms such as Antisocial Personality Disorder (ASPD) [66,67], Borderline Personality Disorder (BPD) [68–70], Attention Deficit/Hyperactivity Disorder (ADHD) [71,72], Intermittent Explosive Disorder (IED) [73], Schizophrenia [74,75], and Bipolar Mood Disorder (BMD) [76,77]. Some of these disorders have different incidences for men and women [78–80], but gender differences are also observed in non-pathological manifestations of aggressive behaviours [2]. This means that gender plays an important role in human aggression [4,81–83], and there are several theoretical models that seek to explain this sexual dimorphism among such distinct cultures [84–86]. Therefore, the knowledge of different types of aggression helps to understand the characteristics underlying gender differences related to aggressive behaviour. 3.1. Types of aggressive behaviour Aggression can take a variety of forms; thus, several classifications and dimensions have been proposed to estimate such differences [87–90]. A classification often used for human aggression is the way in which it is expressed and can be subdivided into direct and indirect aggressions. While the first is characterised by physical or verbal behaviour intended to cause harm to someone [83,91], the second one is characterised by a behaviour intended to harm social relations of an individual or a group [83,88,91]. A significant part of the data on gender differences in human aggression is based on this classification of both types of aggression. Many studies have found differences in aggression types in males and females. Men tend to have a greater propensity for physical and direct aggression, while women tend to use indirect and verbal aggression [88,92–96]. Moreover, there is evidence for a greater discrepancy between genders in school-aged children than in adults [83,93,97], though there are no differences between genders in preschool-aged children [98]. Male children and teenagers are more inclined to express direct aggressive behaviour, especially of the physical type, while girls tend to use indirect aggression and most frequently express social rejection [92,95,96,99]. However, empirical studies and meta-analyses do not completely sustain this hypothesis, since several results point towards little or no difference between genders for indirect aggression [83,84, 97,100]. Furthermore, the female indirect aggression is associated with the data collection method used [101]. However, such studies strongly corroborate the male effect towards direct aggression. This type of aggression is associated with externalising problems, difficulties in relationships with peers and low prosocial behaviour, on the other hand, indirect aggression is associated with internalising issues and a high level of prosocial behaviour [95,101–103]. Moreover, research on this approach has mainly focused on direct aggression (e.g., [104, 105]), and this can bias or undervalue data on female aggression [101, 102], since this may have evolved to be indirect and physically less dangerous [4].

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There is also a functional categorisation, which is useful to understand the psychopathological and neurobiological determining factors of human aggressiveness. Therefore, the type of aggression that is commonly related to an excess or lack of emotional sensitivity [106,107] can be classified as either impulsive (or reactive) or instrumental (or proactive) aggression [108–110]. Impulsive aggression is defined as a hostile act in response to a stimuli perceived as threatening or frustrating [111]. This type of aggression has a strong emotional component and high autonomic arousal [109], besides being associated with low impulse control [112,113] and a biased perception of hostility [114]. When impulsive aggression is disproportional in relation to the triggering stimulus, it is considered an important psychopathological symptom and plays a critical role in several psychiatric disorders [115], e.g. in ASPD and BPD [116,117]. In contrast, instrumental aggression is a deliberately planned behavioural pattern to attain a goal, and whose actions tend to be premeditated and controlled [118–120]. This type of agonist behaviour is related to the occurrence of delinquency, crime, lack of remorse and dominance [87,121,122], but also associates with social competence [108,123] and leadership [106]. Psychopathy, described as a pattern of high occurrence of violent and manipulative behaviours, is frequently considered a pathological expression of instrumental aggression [124] besides the lack of remorse and empathy [118]. In this functional categorisation, males once again tend to show higher levels of aggression in both dimensions, regardless of the age group [91]. However, the aggression level of females is also considered to be high, with differences that are not always significant between genders, mainly for impulsive aggression [83,125]. Regardless of the type of aggression, biological and environmental factors should be considered. 3.2. Peripheral hormones Several lines of research have sought to explain the gender differences in aggression based on hormonal physiology, which presents markedly varied patterns for each gender [126–128,60]. Sex steroid hormones can play a key role in the manifestation and development of agonist behaviours [1,129,130]. Testosterone is considered to be the main androgenic hormone, and it is consistently associated with aggressive behaviour [7,131–133], even in children and adolescents [130,134]. Likewise, early or atypical pre-natal exposure to androgenic steroids can also have an impact on the development of aggressive behaviour [130, 135–138], particularly in girls [5]. Experimental studies have shown that supraphysiological levels of testosterone increase the manifestation of aggression [139–142], while correlation studies associate testosterone with greater impulsiveness [143,144], greater responsiveness of neural circuits related to social aggression [145] and anger [146–149]. However, these results are not evenly found in all studies [117,150]. More than aggression, testosterone is strongly related to dominance behaviour and context of victory in both men and women [5,87,131, 149,151–153]. For men, winning in a competitive situation tends to increase testosterone levels compared to defeat, but this pattern has not been observed in women [38,151,154,155]. These studies support the idea of the winner effect in humans, i.e. there is an increase in aggressiveness and readiness for new confrontations in men that win a competition, and this effect is highly modulated by the testosterone reactivity after a victory [38,155,156]. Therefore, it can be assumed that testosterone is a factor associated with the escalation of aggressiveness among men, with relevant impact in a competitive context, though this is not necessarily true for women [127]. The role of testosterone is not fully established in human aggression, given that several studies have found a weak or inconsistent association among these variables, in addition to large individual variations for both genders [5,87,157,158]. This can be explained, in part, by the modulating effect of cortisol [87,159,160]. Cortisol is the main GC hormone secreted by humans [161], and chronically elevated levels of this hormone can suppress gonad function and synthesis of androgenic steroids

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[162]. Reduced levels of cortisol are related to greater aggressiveness [163], and psychopathic behaviour is related to HPA axis dysfunction [164–167]. Some studies suggest that testosterone elicits an increase in aggressiveness [159,160] and competitiveness [168] when combined with a low level of cortisol. Indeed, the ratio of testosterone and cortisol can regulate social aggression [32,145]. Also, dehydroepiandrosterone (DHEA), which is essentially a direct precursor of testosterone, can be notably relevant for the manifestation of aggressiveness [169], especially when the levels of testosterone are low [129,170]. High levels of DHEA and/or its circulating sulphate form (DHEAS) are correlated with the following: severity of aggressive events [171,172], antisocial behaviour [173], increased aggression in healthy children [174], as well as in boys [172] and girls [175] presenting conduct disorder. The relationship between hormones and aggression is not fully understood in women compared to men. The inconsistency in the data on the relationship between female aggression and androgenic steroids may be explained by the major focus of research on measurement of physical aggression, which may underestimate female aggression. Cashdan [127] found greater probability of women with higher levels of androstenedione, a precursor of sex hormones, to show competitiveness through verbal aggression. It was also shown that there was no relationship between androgenic steroids and physical aggression. This study also indicated that women with higher levels of estradiol had less competitive interactions. Of note, the ovarian production of testosterone, androstenedione and DHEAS reaches the highest levels during the intermediate period of the menstrual cycle, producing almost twice the amount of androstenedione than the adrenal glands, besides all variations in estrogenic hormones [176]. Progesterone, on the other hand, can interfere with HPA axis function [177–179] and influence aggressive behaviour and emotional lability [78,180]. This may contribute directly to the controversy of results regarding female aggression and hormonal secretion. In this context, both oxytocin and vasopressin are implicated in sextypical behaviour [60,181]. Studies with animal models have demonstrated the key role of vasopressin upon aggressive behaviour [182]. There is a positive association between vasopressin levels and rates of aggression and impulsivity, having distinct effects on males and females [183,184]. Additionally, treatment with the V1a vasopressin receptor antagonist decreases aggression in a dose-dependent manner [182]. On the other hand, these effects of vasopressin may depend on personal characteristics, such as gender, age and prior social experiences, and on the type of aggression [183,184]. The scarce human studies on vasopressin suggest social effects similar to those found in animal research. Data from diverse populations have supported the notion that vasopressin influences the sexual dimorphism in aggression [185,186]. These studies have also confirmed that these relations differ for specific types of aggression. A non-clinical study showed that intranasally delivered vasopressin differentially affected facial motor patterns in men and women [181]. In this experiment, the vasopressin enhanced agonistic and affiliative types of responses towards unfamiliar same-sex faces in men and women, respectively. A possible explanation suggests that there is a sex difference in the distribution of vasopressin receptors [187]. Yet, men would have higher vasopressin levels than women [188]. It is not completely clear, however, the relationship that vasopressin has with sex steroids on human aggressive behaviour, although it has been seen that androgenic hormones can strongly influence the vasopressin receptor binding [187,189,190], and that the vasopressin induction of aggression is dependent on the presence of testosterone [191]. Finally, vasopressin influences the HPA axis, mediating the adrenocorticotropic hormone release, acting synergistically with corticotropin-releasing hormone function [192,193]; GC can inhibit the vasopressin synthesis and release [194], but these relationships on aggressiveness have been mostly neglected. Hormone–neuropeptide interactions on sex differences in social behaviours have received more attention only recently; thus, much needs to be elucidated regarding how it influences human aggressiveness.

3.3. Neurobiological mechanisms The neural basis of aggression has consistently been established in recent years. Cerebral regions and neurotransmitters, and their connection with several genes, hormones, and psychiatric disorders, previously identified in animal models or in studies of lesions, have also been investigated in healthy people. Among cortical structures, the Prefrontal Cortex (PFC) is the region that is most extensively associated with impulsive aggression in humans [195,196]. The PFC plays a central role in the control of behaviours, in driving towards a defined goal and in the decision-making process [197,198]. A study showed that patients with ventromedial PFC (vmPFC) lesions had a greater probability of having verbal conflicts and showing aggressiveness when compared to patients with lesions in other cerebral areas and a control group devoid of lesions [199]. In the same study, specific lesions on the Orbitofrontal Cortex (OFC), the region implicated in auto-regulation and impulse control [200], were associated with higher aggression scores. Men with ASPD have shown changes in the OFC, in the Anterior Cingulate Cortex (ACC), in the Insula and in the Amygdala [201–204]. Likewise, patients with BPD [205,206] and IED [73] also presented atypical function characteristics in these regions. Neuroimaging studies have confirmed a dysfunction [73,119,124,207–211] and reduction of the volume [201,203,204,212,213] of the OFC, ACC and vmPFC in people with aggressive behaviour. In general, testosterone has been observed to alter OFC function [145,214–216], which can increase impulsive aggression [207]. This is a possible explanation for the escalation of aggression caused by the secretion of testosterone after achieving success in a competition, i.e. the increase of testosterone decreases OFC activity, and consequently, increases the predisposition to react aggressively in future competitions. There has been growing evidence supporting the amygdala function as one of the most important regions for aggression in humans [217]. The amygdala, which is involved in the processing of biologically relevant stimuli and emotional reactions [218], and the PFC are reciprocally connected [219,220]. The OFC regulates the amygdala activity [221], which is also influenced by sex steroids [126]. Testosterone increases the neural activity in the amygdala [146,215,222] and hinders its connectivity with the OFC [214,216]. On the other hand, cortisol has an inverse correlation with amygdala activation [223]. In other words, the testosterone/cortisol ratio can increase the bottom-up reaction (i.e., emphasising amygdala activation) and impair the top-down control (reducing the inhibitory action of the OFC and ACC) of impulsive aggression. It is important to highlight that amygdala activation can be an indirect consequence of lack of inhibitory control of the OFC [214]; however, the direct action of androgenic receptors, present in the PFC [224] and in the amygdala [225], still requires further elucidation in humans. Indeed, testosterone exerts its main action through intracellular androgenic receptors, although it can also be metabolised to androstenediol, which modulates the GABAA receptors [226,227] (Fig. 1). There is a relevant sexual dimorphism in the cerebral structures previously mentioned [228,229]. Evidence has supported the fact that progesterone influences amygdala reactivity, with an inverted “U” shaped relation. This hormone increases the amygdala reactivity in intermediate doses and decreases it in higher doses, it also emphasises the amygdala–PFC connectivity; however, in this case the interconnection with the medial PFC is more affected, which is different from the pattern related to testosterone [126,216]. Disruptions in the PFC–amygdala connections are associated with many psychiatric disorders [230–232] and violent acts [73,208,233]. It is worth emphasising that progesterone also influences GABAA receptors through its metabolite allopregnanolone [234,235]. Other structures of the limbic system, such as the hippocampus and the hypothalamus, are also highly relevant for aggressive behaviour, but causal studies in humans are still scarce. Similar to data found in preclinical studies, human aggression is related to the inhibitory action of the GABA neurotransmitter. Alcohol is a positive allosteric modulator of the GABAA receptor [236], and its


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Fig. 1. Steroid hormones and the neurobiology of human aggression. Aggressive behaviour is determined by a cascade of physiological changes, which includes GABAergic and serotonergic systems, as well as sexual neurosteroids, resulting in amygdala hyperactivation and hypofunction of prefrontal cortex structures (i.e., ventromedial prefrontal cortex, orbitofrontal cortex and anterior cingulated cortex) responsible for impulse control. Hormones play a key role in human aggression. Intermediate levels of progesterone, high levels of testosterone and low levels of cortisol are key factors for aggression. The effect of the positive allosteric modulators of GABAA receptors is associated with aggressive behaviours. Intermediate levels of allopregnanolone and high levels of androstenediol, both endogenous positive modulators of GABAA receptors, can increase aggressiveness. Furthermore, GC can reduce the manifestation of aggressive behaviour caused by the positive modulators of the GABAA receptor. Decreased serotonergic activity can lead to aggressive behaviour in humans. The density of 5-HT1A receptors is associated with aggression, mainly with a decrease of its density in the prefrontal cortex and an increase in the raphe nuclei.

recreational intake or abuse often increases the occurrence of aggressive behaviours [237–239]. This also occurs with most benzodiazepines when not administered in high doses [240,241]. However, benzodiazepines are also an important class of drugs known for their sedative and tranquillizer properties [242,243], and are extensively used to restrain violent patients [244,245]. Bond and colleagues [246] showed that, even among patients that reported a perceptual decrease in hostility after eight weeks of treatment with alprazolam, there was an increase in aggressive responses during a behavioural task. These apparently controversial results are explained by a dose-dependent action of these substances on the GABAA receptor, with moderate levels being related to aggression [247,248]. The paradoxical effect of the endogenous positive modulators of GABAA receptor has been studied recently, and several hypotheses have been raised to explain these findings. Allopregnanolone is the most abundant and efficient endogenous positive modulator of the GABAA receptor [234,235] and women with premenstrual dysphoria, besides having low levels of allopregnanolone during the luteal phase [249–251], still exhibit decreased GABAA receptor sensitivity [252,253]. The order of magnitude for severe or moderate symptoms in premenstrual dysphoric disorder (PMDD), generally associated with irritability and emotional instability [251], is proportional to that observed in people who are also severely or moderately susceptible to the paradoxical effects of positive modulators of the GABAA receptor [254]. This effect suggests an inverted “U” shaped relation [248], as well as the amygdala reactivity pattern seen for progesterone [126]. Moreover, the serum concentration of allopregnanolone and the administration of medroxyprogesterone and natural progesterone follow this same biphasic pattern for the manifestation of negative moods in women [254]. In rodents, the mRNA expression of 5α-reductase(I), an enzyme responsible for the biosynthesis of allopregnanolone, is negatively regulated by the chronic administration of testosterone propionate in several corticolimbic structures, especially the amygdala [247]. This data suggests that testosterone reduces the biosynthesis of allopregnanolone, and it could be a determining factor in gender

differences in aggression; however, these results still need to be demonstrated in humans. Stress can be another decisive factor for the sensitivity of the GABAA receptor to the effects of positive modulators. It has been demonstrated in animal models that corticosterone (the main GC secreted by rodents [161]) reduces the manifestation of aggressive behaviour caused by the positive modulators of the GABAA receptor, including the benzodiazepines and allopregnanolone [255]. In fact, there is evidence associating the luteal phase in patients with PMDD with deregulation of the HPA axis [178,249]. In a study performed by Kirschbaum and colleagues [177], it was observed that, during the luteal phase, women presented similar secretion levels of cortisol compared to men in response to a stressful event. These levels were different from those of women in the follicular phase and women using oral contraceptives. Moreover, stressful events increase the levels of allopregnanolone [234]. These findings might help to elucidate the modulation action of cortisol in testosterone associated-aggression [159,160,207], given the fact that testosterone can modulate the GABAA receptor [226]. These results lead to a hypothesis regarding the role of GC in inhibitory feedback for the escalation of aggressive behaviour. This means that the GC levels rise after a conflict and can interfere with the endogenous positive modulators of the GABAA receptors, and consequently, reduce impulsive aggression. In addition, this hypothesis can explain the violent behaviour of psychopathic individuals because the HPA axis is dysfunctional in these persons, and it can escalate aggression because of a failure in this inhibitory feedback mechanism. The serotonergic system is the focus of many lines of research on aggression and is certainly one of the most important neurotransmitters in the manifestation of this type of behaviour. Traditionally, dysfunction of 5-HT activity is related to increased levels of impulsiveness [71, 256–258] and aggressiveness [259,260]. It has been shown that the use of selective serotonin reuptake inhibitors (SSRI) has a significant clinical effect in reducing violent behaviour [261–263], and psychiatric patients with a history of aggression usually have changes in serotonergic

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neurotransmission [117,257,258,264]. A meta-analysis performed by Moore and colleagues [265] concluded that the 5-HT metabolite (5HIAA) level in the cerebrospinal fluid was consistently low in people with antisocial behaviour, regardless of psychiatric disorder or gender. However, recent studies support the idea that the serotonergic action can also be positively associated with aggressiveness [266,267]. The activation and distribution of different serotonergic receptors are relevant for their effect on aggressiveness [268]. The presynaptic somatodendritic 5-HT1A receptors are located in the 5-HT neurones of the raphe nuclei and postsynaptically in several brain regions, such as the PFC, amygdala and hippocampus [267,269]. This receptor inhibits the activity of target neurones and is abundantly expressed in the PFC [269]. In people with a high level of aggression, there is a greater density of postsynaptic 5-HT1A receptors in the PFC, including OFC, vmPFC, and ACC [270], regions related with impulse control. Several studies have corroborated that the density of the 5-HT transporter (5HTT), as well as induction of serotonergic stimulation, are associated with changes in the OFC, vmPFC and ACC in aggressive patients [271–274]. In general, the cingulated cortex is the cerebral region with the highest density of serotonergic receptors [275]. There is not much evidence supporting the direct role of 5-HT in gender differences regarding manifestation of aggression in humans [265]. However, the serotonergic action in aggressive behaviour can be regulated by the concentration of sex steroids [270,276]. It is important to highlight that the use of an SSRI can increase the levels of allopregnanolone and attenuate aggression induced by testosterone propionate, even with the use of doses incapable of inhibiting the reuptake of 5-HT [247,277]. Variation in the levels of sex hormones during the menstrual cycle is followed by changes in the distribution of 5-HT1A receptors [270]. In addition, the use of an SSRI induces an increase of cortisol in people with high levels of aggression [278]. Also, 5-HT precursors stimulate the secretion of cortisol, as well as several drugs, including the 5-HT1A receptor agonists [279–281]. On the other hand, a high secretion of cortisol can interfere with the serotonergic system, reducing tryptophan through its interaction with tryptophan pyrrolase, the main enzyme that metabolises tryptophan [282]. In fact, low levels of 5-HT, when associated with a high testosterone/cortisol ratio, can predict the manifestation of aggressive behaviour [32]. Likewise, pharmacological and neurobiological findings suggest an interaction between 5-HT and vasopressin in control of aggression [182,283]. An increase in 5-HT yields a fall in vasopressin levels in the anterior and ventrolateral hypothalamus, along with aggression [185,284]. In animal models, many brain regions associated with aggressiveness are known to contain 5-HT and vasopressin activities, like the hypothalamus [284], amygdala, PFC and bed nucleus of the stria terminalis (BNST) [283], which has a role in gender and sex-typical behaviour: human BNST has a clear sex dimorphism [285]. However, these findings are incipient to humans, and further studies in this area are definitely warranted. 3.4. Genetic bases Many studies approach the genetic influences related to the serotonergic system, as well as the other monoamines, on impulsive aggression and emotional regulation. Monoamine Oxidase A (MAOA) is an enzyme involved in the degradation of monoamines, especially 5-HT [286]. The allele responsible for low expression of MAOA (MAOAL) is epidemiologically correlated with a higher probability of the occurrence of aggression and impulsive behaviour [287–289]. A magnetic resonance neuroimaging study showed structural and functional corticolimbic alterations related to the MAOAL genotype [290]. Meyer-Lindenberg and colleagues [290] showed a decrease in the cingulate cortex, insula and hypothalamus volumes, a hyperactivation of the amygdala and a hypoactivation of the cingulate cortex and OFC in MAOAL allele carriers for both genders. Moreover, this study provided evidence for an important gender effect, i.e. an increase in the OFC volume and hyperactivation

of the amygdala and hippocampus. An impairment of the amygdala–OFC connectivity, which occurred only in men with low MAOA expression, was also observed. Experimental studies have confirmed that low MAOA activity can predict the occurrence of impulsive aggression as a reaction to a provocation [291], which can be explained by hypersensitivity to negative social experiences [292]. Transversal and prospective results corroborate the deleterious effects of low MAOA activity in males, especially when it co-occurs with stressful events in childhood [287,289, 293–296]. The MAOA gene is located on the X chromosome [297], causing a male hemizygous for this gene. Then, the sexual differences in the manifestation of agonist behaviour related to low MAOA activity could be explained by the X chromosome inactivation in women, a characteristic that can exacerbate sexual dimorphism [298]. Research on the influence of MAOA has been particularly relevant for the understanding of gene– environment interaction, since the role of this enzyme is linked to emotional processing, and occurrence of early exposure to stress leads to an unfavourable prognosis associated with violence in MAOAL allele carriers [287,294]. Similar findings have been reported when investigating the role of the functional polymorphism related to the 5-HT transporter. The 5HT transporter gene (5HTTLPR), which is responsible for low transcriptional activity, and consequently, decreased 5-HT reuptake, has been associated with the occurrence of violent acts [296,299,300]. Other studies have observed that HTTLPR carriers have decreased ACC and amygdala volumes, in addition to connectivity impairment among these structures [301], as well as higher amygdala activity in response to emotional stimuli [302]. Furthermore, it has been shown that violent individuals have a lower availability of 5HTT in the ACC region [274]. However, these results are still incipient and inconclusive for humans. The same is true for the polymorphism effects of the tryptophan hydroxylase enzyme, which has also inconsistently been associated with human aggression, and more empiric evidence is required [303]. 3.5. Perspectives Gender is a factor that plays a key role in human aggression. Crimes and violent acts have a high prevalence in males [303]. However, social and cultural aspects may significantly interfere with the distinct expression of aggressiveness [86]. For example, a high population density, when associated with a decrease of available resources, might be a significant intervening variable for the occurrence of violent acts [304]. Moreover, physical punishment, maladaptive parenting and social isolation can negatively influence the development of aggressive behaviour in children [287,305]. Gene–environment interactions are critical for the establishment of pathological aggressiveness [306]. There are other factors that can also influence human aggressive behaviour and hinder the comprehension of mechanisms underlying gender differences. The role of the dopaminergic system, which interacts with 5-HT [115] and can be modulated directly or indirectly by steroid hormones [307–309], needs to be properly tested in humans. Similarly, the aromatase activity in the conversion of testosterone into estradiol requires empiric evidence to corroborate its function in human aggression. In summary, human aggression can be considered a relevant evolutionary adaptation for survival and social interaction for both genders, though, when the reaction is disproportionate to the triggering stimulus, it can be considered antisocial and maladaptive. Aggressive behaviour is determined by a cascade of physiological changes, which includes serotonergic, GABAergic, and dopaminergic systems, as well as several neurosteroids, resulting in amygdala hyperactivation and hypofunction of PFC structures responsible for impulse control. The understanding of the physiological basis and behavioural determinants of different types of aggression is fundamental for the establishment of procedures that could minimise the personal and social harm caused by violent acts. However, findings based on gender patterns and manifestations of human aggression are still emerging and require further research.


4. Conclusions This review aimed to provide an overview of behavioural, neurobiological and hormonal bases of sex-related differences in aggressive behaviour (a brief summary is provided in Table 1). Converging evidence has identified a key role for the interactions of neurotransmitters, neuromodulators and hormonal systems in aggression and violent Table 1 A summary of the main effects of steroid hormones, neuromodulators and neurotransmitters on sexually dimorphic aggressive behaviour. Testosterone (androgenic hormone) ↑ Aggression (in high levels) ↑ Impulsivity and anger ↑ Dominance and competitivity ↑ Winner effect and readiness for confrontations ↓ OFC activity ↑ Amygdala activity ↓ OFC–amygdala connectivity Can be metabolised to androstenediol ↓ Biosynthesis of allopregnanolone Progesterone (progestogenic hormone) ↑ Aggression (in intermediated levels) Inverted “U” shaped relation with amygdala reactivity Affects medial PFC–amygdala connectivity Can be metabolised to allopregnanolone Cortisol (glucocorticoid hormone) ↑ Aggression (in low levels) Interacts with testosterone effects ↓ Gonadal functions ↓ Synthesis of sex steroids ↓ Amygdala activity Alters PFC activity Influences the sensitivity of GABAA receptor to positive allosteric modulator Can interfere with 5-HT system DHEA/DHEAS (androgenic hormone) Interacts with testosterone effects ↑ Aggression Vasopressin (neurohypophysial hormone) ↑ Aggression ↑ Impulsivity Is characteristic-dependent Is sexual dimorphic Interacts with testosterone effects Interacts with HPA axis Can interfere with 5-HT system Allopregnanolone (neurosteroid) Main endogenous positive allosteric modulator of GABAA receptor ↑ Aggression in intermediated levels GABA (neurotransmitter) ↑ Aggression in intermediated levels Inverted “U” shaped of positive allosteric modulators of the GABAA receptor Paradoxical effect of the endogenous positive allosteric modulators of GABAA receptors on aggression Serotonin (neurotransmitter) Low levels ↑ aggression and impulsivity Higher density of 5-HT1A receptor in OFC, vmPFC and ACC is associated with aggression Is modulated by sex steroids Can ↑ allopregnanolone ↓ Aggression induced by testosterone ↑ Cortisol ↓ Vasopressin OFC = Orbitofrontal Cortex; PFC = Prefrontal Cortex; GABA = γ-Aminobutyric Acid; 5HT = serotonin; HPA = hypothalamic–pituitary–adrenal axis; vmPFC = Ventromedial Prefrontal Cortex; ACC = Anterior Cingulate Cortex.

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behaviours. The comprehension of the different mechanisms underlying aggression in each gender has grown substantially in the last decades, and it is a matter of both clinical and ecological importance. Clinically, the elucidation of the physiological pathways associated with aggression in men and women might allow for differential drug treatments for each case, targeting specific molecules and receptors to maximise efficiency. The knowledge from behavioural and molecular research has been proven to be significant for improving the understanding of the origins and determinants of aggression. Thus, here, we highlighted the major contributions of sex neurosteroids to manifestations of sexual dimorphism of aggression in human and nonhuman primates, alongside with serotonin and GABA neurotransmissions and genetic factors. However, more data on how these factors can affect early in brain development, both directly or through their interactions is warranted. Furthermore, the role of dopamine, vasopressin and oxytocin in this interaction issue, as well as the environmental contingencies, may help to enhance understanding and expand their applications for managing and more efficiently avoiding the social costs of aggression and violent acts.

References [1] J. van Honk, E. Harmon-Jones, B.E. Morgan, D.J.L.G. Schutter, Socially explosive minds: the triple imbalance hypothesis of reactive aggression, J. Pers. 78 (2010) 67–94. http://dx.doi.org/10.1111/j.1467-6494.2009.00609.x. [2] J. Archer, The nature of human aggression, Int. J. Law Psychiatry 32 (2009) 202–208. http://dx.doi.org/10.1016/j.ijlp.2009.04.001. [3] K.A. Miczek, E.W. Fish, J.F. De Bold, R.M.M. De Almeida, Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and gamma-aminobutyric acid systems, Psychopharmacology (Berl.) 163 (2002) 434–458. http://dx.doi.org/10.1007/s00213-002-1139-6. [4] A. Campbell, Staying alive: evolution, culture, and women's intrasexual aggression, Behav. Brain Sci. 22 (1999) 203–252. http://dx.doi.org/10.1017/S0140525X99001818. [5] J. Archer, Testosterone and human aggression: an evaluation of the challenge hypothesis, Neurosci. Biobehav. Rev. 30 (2006) 319–345. http://dx.doi.org/10.1016/ j.neubiorev.2004.12.007. [6] I.S. Bernstein, T.P. Gordon, The function of aggression in primate societies, Am. Sci. 62 (1974) 304–311. http://dx.doi.org/10.1016/0022-5193(76)90072-2. [7] A. Mazur, A. Booth, Testosterone and dominance in men, Behav. Brain Sci. 21 (1998) 353–397. http://dx.doi.org/10.1017/S0140525X98001228. [8] E.G. Krug, J.A. Mercy, L.L. Dahlberg, A.B. Zwi, R. Lozano, World report on violence and health, N. S. W. Public Health Bull. 13 (2002) 190. http://dx.doi.org/10.1071/ NB02075. [9] N.J. Kassebaum, A. Bertozzi-Villa, M.S. Coggeshall, K.A. Shackelford, C. Steiner, K.R. Heuton, et al., Global, regional and national levels of age-specific mortality and 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013, Lancet 385 (2014) 117–171. http://dx.doi.org/10.1016/ S0140-6736(14)61682-2. [10] J.M. Plavcan, Sexual size dimorphism, canine dimorphism, and male–male competition in primates: where do humans fit in? Hum. Nat. 23 (2012) 45–67. http://dx. doi.org/10.1007/s12110-012-9130-3. [11] P.E. Honess, C.M. Marin, Behavioural and physiological aspects of stress and aggression in nonhuman primates, Neurosci. Biobehav. Rev. 30 (2006) 390–412. http:// dx.doi.org/10.1016/j.neubiorev.2005.04.003. [12] R. Wrangham, D. Peterson, Demonic Males: Apes and the Origins of Human Violence, Houghton Mifflin, Boston, 1996. [13] D.R. Carrier, The short legs of great apes: evidence for aggressive behavior in australopiths, Evolution (N. Y.) 61 (2007) 596–605. http://dx.doi.org/10.1111/j. 1558-5646.2007.00061.x. [14] F.B.M. de Waal, Primates — a natural heritage of conflict resolution, Science 289 (2000) 586–590. http://dx.doi.org/10.1126/science.289.5479.586. [15] B.M.F. Galdikas, Subadult male orangutan sociality and reproductive behavior at Tanjung Puting, Am. J. Primatol. 8 (1985) 87–99. http://dx.doi.org/10.1002/ajp. 1350080202. [16] J.C. Mitani, D.P. Watts, S.J. Amsler, Lethal intergroup aggression leads to territorial expansion in wild chimpanzees, Curr. Biol. 20 (2010) R507–R508. http://dx.doi. org/10.1016/j.cub.2010.04.021. [17] R.W. Wrangham, L. Glowacki, Intergroup aggression in chimpanzees and war in nomadic hunter–gatherers: evaluating the chimpanzee model, Hum. Nat. 23 (2012) 5–29. http://dx.doi.org/10.1007/s12110-012-9132-1. [18] R.W. Wrangham, M.L. Wilson, M.N. Muller, Comparative rates of violence in chimpanzees and humans, Primates 47 (2006) 14–26. http://dx.doi.org/10.1007/ s10329-005-0140-1. [19] D.P. Watts, M. Muller, S.J. Amsler, G. Mbabazi, J.C. Mitani, Lethal intergroup aggression by chimpanzees in Kibale National Park, Uganda, Am. J. Primatol. 68 (2006) 161–180. http://dx.doi.org/10.1002/ajp.20214. [20] M. Muller, Agonistic relations among Kanyawara chimpanzees, in: C. Boesch, G. Hohmann, L. Marchant (Eds.), Behav. Divers, Cambridge University Press, Chimpanzees Bonobos, 2002, pp. 112–124.

130


[21] K.J. Hockings, G. Yamakoshi, A. Kabasawa, T. Matsuzawa, Attacks on local persons by chimpanzees in Bossou, Republic of Guinea: long-term perspectives, Am. J. Primatol. 72 (2010) 887–896. http://dx.doi.org/10.1002/ajp.20784. [22] B. Hare, V. Wobber, R. Wrangham, The self-domestication hypothesis: evolution of bonobo psychology is due to selection against aggression, Anim. Behav. 83 (2012) 573–585. http://dx.doi.org/10.1016/j.anbehav.2011.12.007. [23] M. Bermejo, Home-range use and intergroup encounters in western gorillas (Gorilla g. gorilla) at Lossi forest, North Congo, Am. J. Primatol. 64 (2004) 223–232. http://dx.doi.org/10.1002/ajp.20073. [24] B.J. Bradley, M.M. Robbins, E.A. Williamson, H.D. Steklis, N.G. Steklis, N. Eckhardt, et al., Mountain gorilla tug-of-war: silverbacks have limited control over reproduction in multimale groups, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 9418–9423. http://dx.doi.org/10.1073/pnas.0502019102. [25] P. Sicotte, The function of male aggressive displays towards females in mountain gorillas, Primates 43 (2002) 277–289. http://dx.doi.org/10.1007/BF02629603. [26] P.K. Pullen, Preliminary comparisons of male/male interactions within bachelor and breeding groups of western lowland gorillas (Gorilla gorilla gorilla), Appl. Anim. Behav. Sci. 90 (2005) 143–153. [27] E. Palagi, E. Chiarugi, G. Cordoni, Peaceful post-conflict interactions between aggressors and bystanders in captive lowland gorillas (Gorilla gorilla gorilla), Am. J. Primatol. 70 (2008) 949–955. http://dx.doi.org/10.1002/ajp.20587. [28] B.A. Beisner, B. McCowan, Policing in nonhuman primates: partial interventions serve a prosocial conflict management function in rhesus macaques, PLoS One 8 (2013) e77369. http://dx.doi.org/10.1371/journal.pone.0077369. [29] T. Tajima, H. Kurotori, Nonaggressive interventions by third parties in conflicts among captive Bornean orangutans (Pongo pygmaeus), Primates 51 (2010) 179–182. http://dx.doi.org/10.1007/s10329-009-0180-z. [30] B. McCowan, B.A. Beisner, J.P. Capitanio, M.E. Jackson, A.N. Cameron, S. Seil, et al., Network stability is a balancing act of personality, power, and conflict dynamics in rhesus macaque societies, PLoS One 6 (2011) e22350. http://dx.doi.org/10. 1371/journal.pone.0022350. [31] R.M. Sapolsky, The influence of social hierarchy on primate health, Science 308 (2005) 648–652. http://dx.doi.org/10.1126/science.1106477 (80-.). [32] E.R. Montoya, D. Terburg, P.A. Bos, J. van Honk, Testosterone, cortisol, and serotonin as key regulators of social aggression: a review and theoretical perspective, Motiv. Emot. 36 (2012) 65–73. http://dx.doi.org/10.1007/s11031-011-9264-3. [33] Y. Yamanashi, N. Morimura, Y. Mori, M. Hayashi, J. Suzuki, Cortisol analysis of hair of captive chimpanzees (Pan troglodytes), Gen. Comp. Endocrinol. 194 (2013) 55–63. http://dx.doi.org/10.1016/j.ygcen.2013.08.013. [34] K.L. Bales, J.A. French, C.M. Hostetler, J.M. Dietz, Social and reproductive factors affecting cortisol levels in wild female golden lion tamarins (Leontopithecus rosalia), Am. J. Primatol. 67 (2005) 25–35. http://dx.doi.org/10.1002/ajp.20167. [35] A.C.S.R. Albuquerque, M.B.C. Sousa, H.M. Santos, T.E. Ziegler, Behavioral and hormonal analysis of social relationships between oldest females in a wild monogamous group of common marmosets (Callithrix jacchus), Int. J. Primatol. 22 (2001) 631–645. http://dx.doi.org/10.1023/A:1010741702831. [36] T.E. Ziegler, M.B.C. Sousa, Parent–daughter relationships and social controls on fertility in female common marmosets, Callithrix jacchus, Horm. Behav. 42 (2002) 356–367. http://dx.doi.org/10.1006/hbeh.2002.1828. [37] S.A. Cavigelli, T. Dubovick, W. Levash, A. Jolly, A. Pitts, Female dominance status and fecal corticoids in a cooperative breeder with low reproductive skew: ring-tailed lemurs (Lemur catta), Horm. Behav. 43 (2003) 166–179. http://dx.doi.org/10. 1016/S0018-506X(02)00031-4. [38] J.M. Carré, J.A. Campbell, E. Lozoya, S.M.M. Goetz, K.M. Welker, Changes in testosterone mediate the effect of winning on subsequent aggressive behaviour, Psychoneuroendocrinology 38 (2013) 2034–2041. http://dx.doi.org/10.1016/j. psyneuen.2013.03.008. [39] K.L.K. Tamashiro, M.M.N. Nguyen, R.R. Sakai, Social stress: from rodents to primates, Front. Neuroendocrinol. 26 (2005) 27–40. http://dx.doi.org/10.1016/j. yfrne.2005.03.001. [40] M.E. Sobolewski, J.L. Brown, J.C. Mitani, Female parity, male aggression, and the Challenge Hypothesis in wild chimpanzees, Primates 54 (2013) 81–88. http://dx. doi.org/10.1007/s10329-012-0332-4. [41] L. Michael Romero, Seasonal changes in plasma glucocorticoid concentrations in free-living vertebrates, Gen. Comp. Endocrinol. 128 (2002) 1–24. http://dx.doi. org/10.1016/S0016-6480(02)00064-3. [42] C. Girard-Buttoz, M. Heistermann, E. Rahmi, M. Agil, P. Ahmad Fauzan, A. Engelhardt, Costs of mate-guarding in wild male long-tailed macaques (Macaca fascicularis): physiological stress and aggression, Horm. Behav. 66 (2014) 637–648. http://dx.doi.org/10.1016/j.yhbeh.2014.09.003. [43] S.A. Cavigelli, M.E. Pereira, Mating season aggression and fecal testosterone levels in male ring-tailed lemurs (Lemur catta), Horm. Behav. 37 (2000) 246–255. http://dx.doi.org/10.1006/hbeh.2000.1585. [44] J. Cristóbal-Azkarate, R. Chavira, L. Boeck, E. Rodríguez-Luna, J.J. Veàl, Testosterone levels of free-ranging resident mantled howler monkey males in relation to the number and density of solitary males: a test of the challenge hypothesis, Horm. Behav. 49 (2006) 261–267. http://dx.doi.org/10.1016/j. yhbeh.2005.07.015. [45] H.D. Steklis, G.L. Brammer, M.J. Raleigh, M.T. McGuire, Serum testosterone, male dominance, and aggression in captive groups of vervet monkeys (Cercopithecus aethiops sabaeus), Horm. Behav. 19 (1985) 154–163. http://dx.doi.org/10.1016/ 0018-506X(85)90015-7. [46] K.L. Bales, J.A. French, J. McWilliams, R.A. Lake, J.M. Dietz, Effects of social status, age, and season on androgen and cortisol levels in wild male golden lion tamarins (Leontopithecus rosalia), Horm. Behav. 49 (2006) 88–95. http://dx.doi.org/10.1016/ j.yhbeh.2005.05.006.

[47] P.E. Honess, C.M. Marin, Enrichment and aggression in primates, Neurosci. Biobehav. Rev. 30 (2006) 413–436. http://dx.doi.org/10.1016/j.neubiorev.2005. 05.002. [48] V. Reinhardt, C. Liss, C. Stevens, Social housing of previously single-caged macaques: what are the options and the risks? Anim. Welf. 4 (1995) 307–328 (http://www. ingentaconnect.com/content/ufaw/aw/1995/00000004/00000004/art00005). [49] J. Balcombe, H. Ferdowsian, D. Durham, Self-harm in laboratory-housed primates: where is the evidence that the Animal Welfare Act amendment has worked? J. Appl. Anim. Welf. Sci. 14 (2011) 361–370. http://dx.doi.org/10.1080/10888705. 2011.600667. [50] J.L. Weed, P.O. Wagner, R. Byrum, S. Parrish, M. Knezevich, D.A. Powell, Treatment of persistent self-injurious behavior in rhesus monkeys through socialization: a preliminary report, Contemp. Top. Lab. Anim. Sci. 42 (2003) 21–23. [51] A. Pusey, C. Murray, W. Wallauer, M. Wilson, E. Wroblewski, J. Goodall, Severe aggression among female Pan troglodytes schweinfurthii at Gombe National Park, Tanzania, Int. J. Primatol. 29 (2008) 949–973. http://dx.doi.org/10.1007/s10764008-9281-6. [52] B.M. Bezerra, A. Da Silva Souto, N. Schiel, Infanticide and cannibalism in a freeranging plurally breeding group of common marmosets (Callithrix jacchus), Am. J. Primatol. 69 (2007) 945–952. http://dx.doi.org/10.1002/ajp.20394. [53] S.M. Kahlenberg, M. Emery Thompson, R.W. Wrangham, Female competition over core areas in Pan troglodytes schweinfurthii, Kibale National Park, Uganda, Int. J. Primatol. 29 (2008) 931–947. http://dx.doi.org/10.1007/s10764-008-9276-3. [54] J.M. Setchell, L.A. Knapp, E.J. Wickings, Violent coalitionary attack by female mandrills against an injured alpha male, Am. J. Primatol. 68 (2006) 411–418. http:// dx.doi.org/10.1002/ajp.20234. [55] A.E. Pusey, K. Schroepfer-Walker, Female competition in chimpanzees, Philos. Trans. R. Soc. Lond. B Biol. Sci. 368 (2013) 20130077. http://dx.doi.org/10.1098/ rstb.2013.0077. [56] M.L. Wilson, R.W. Wrangham, Intergroup relations in chimpanzees, Annu. Rev. Anthropol. 32 (2003) 363–392. http://dx.doi.org/10.1146/annurev.anthro.32. 061002.120046. [57] S.M. Kahlenberg, M.E. Thompson, M.N. Muller, R.W. Wrangham, Immigration costs for female chimpanzees and male protection as an immigrant counterstrategy to intrasexual aggression, Anim. Behav. 76 (2008) 1497–1509. http://dx.doi.org/10. 1016/j.anbehav.2008.05.029. [58] B.A. Beisner, L.A. Isbell, Factors affecting aggression among females in captive groups of rhesus macaques (Macaca mulatta), Am. J. Primatol. 73 (2011) 1152–1159. http://dx. doi.org/10.1002/ajp.20982. [59] J.D. Higley, S.T. King, M.F. Hasert, M. Champoux, S.J. Suomi, M. Linnoila, Stability of interindividual differences in serotonin function and its relationship to severe aggression and competent social behavior in rhesus macaque females, Neuropsychopharmacology 14 (1996) 67–76. http://dx.doi.org/10.1016/ S0893-133X(96)80060-1. [60] A. Campbell, Attachment, aggression and affiliation: the role of oxytocin in female social behavior, Biol. Psychol. 77 (2008) 1–10. http://dx.doi.org/10.1016/j. biopsycho.2007.09.001. [61] V. Michopoulos, M. Checchi, D. Sharpe, M.E. Wilson, Estradiol effects on behavior and serum oxytocin are modified by social status and polymorphisms in the serotonin transporter gene in female rhesus monkeys, Horm. Behav. 59 (2011) 528–535. http://dx.doi.org/10.1016/j.yhbeh.2011.02.002. [62] M. Birger, M. Swartz, D. Cohen, Y. Alesh, C. Grishpan, M. Kotelr, Aggression: the testosterone–serotonin link, Isr. Med. Assoc. J. 5 (2003) 653–658 (http://www.ncbi. nlm.nih.gov/pubmed/14509157). [63] G. Ambar, S. Chiavegatto, Anabolic-androgenic steroid treatment induces behavioral disinhibition and downregulation of serotonin receptor messenger RNA in the prefrontal cortex and amygdala of male mice, Genes Brain Behav. 8 (2009) 161–173. http://dx.doi.org/10.1111/j.1601-183X.2008.00458.x. [64] C.J. Ferguson, K.M. Beaver, Natural born killers: the genetic origins of extreme violence, Aggress. Violent Behav. 14 (2009) 286–294. http://dx.doi.org/10.1016/j.avb. 2009.03.005. [65] C.A. Anderson, B.J. Bushman, Human aggression, Annu. Rev. Psychol. 53 (2002) 27–51. http://dx.doi.org/10.1146/annurev.psych.53.100901.135231. [66] R.J. Blair, Neurocognitive models of aggression, the antisocial personality disorders, and psychopathy, J. Neurol. Neurosurg. Psychiatry 71 (2001) 727–731. http://dx. doi.org/10.1136/jnnp.71.6.727. [67] A. Fossati, E.S. Barratt, S. Borroni, D. Villa, F. Grazioli, C. Maffei, Impulsivity, aggressiveness, and DSM-IV personality disorders, Psychiatry Res. 149 (2007) 157–167. http://dx.doi.org/10.1016/j.psychres.2006.03.011. [68] J.K. Gollan, R. Lee, E.F. Coccaro, Developmental psychopathology and neurobiology of aggression, Dev. Psychopathol. 17 (2005) 1151–1171. http://dx.doi.org/10.1017/ S0954579405050546. [69] M.S. McCloskey, A.S. New, L.J. Siever, M. Goodman, H.W. Koenigsberg, J.D. Flory, et al., Evaluation of behavioral impulsivity and aggression tasks as endophenotypes for borderline personality disorder, J. Psychiatr. Res. 43 (2009) 1036–1048. http://dx.doi.org/ 10.1016/j.jpsychires.2009.01.002. [70] P.H. Soloff, L. Chiappetta, N.S. Mason, C. Becker, J.C. Price, Effects of serotonin-2A receptor binding and gender on personality traits and suicidal behavior in borderline personality disorder, Psychiatry Res. 222 (2014) 140–148. http://dx.doi.org/10. 1016/j.pscychresns.2014.03.008. [71] R.D. Oades, J. Lasky-Su, H. Christiansen, S.V. Faraone, E.J. Sonuga-Barke, T. Banaschewski, et al., The influence of serotonin- and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/ hyperactivity disorder (ADHD): findings from a family-based association test (FBAT) analysis, Behav. Brain Funct. 4 (2008) 48. http://dx.doi.org/10.1186/17449081-4-48.

R.M.M. de Almeida et al. / Physiology & Behavior 143 (2015) 121–135 [72] W. Retz, M. Rösler, The relation of ADHD and violent aggression: what can we learn from epidemiological and genetic studies? Int. J. Law Psychiatry 32 (2009) 235–243. http://dx.doi.org/10.1016/j.ijlp.2009.04.006. [73] E.F. Coccaro, M.S. McCloskey, D.A. Fitzgerald, K.L. Phan, Amygdala and orbitofrontal reactivity to social threat in individuals with impulsive aggression, Biol. Psychiatry 62 (2007) 168–178. http://dx.doi.org/10.1016/j.biopsych.2006.08.024. [74] M. Soyka, Neurobiology of aggression and violence in schizophrenia, Schizophr. Bull. 37 (2011) 913–920. http://dx.doi.org/10.1093/schbul/sbr103. [75] M.J. Hoptman, D. D'Angelo, D. Catalano, C.J. Mauro, Z.E. Shehzad, A.M.C. Kelly, et al., Amygdalofrontal functional disconnectivity and aggression in schizophrenia, Schizophr. Bull. 36 (2010) 1020–1028. http://dx.doi.org/10.1093/schbul/sbp012. [76] J.L. Garno, N. Gunawardane, J.F. Goldberg, Predictors of trait aggression in bipolar disorder, Bipolar Disord. 10 (2008) 285–292. http://dx.doi.org/10.1111/j.13995618.2007.00489.x. [77] K. Látalová, Bipolar disorder and aggression, Int. J. Clin. Pract. 63 (2009) 889–899. http://dx.doi.org/10.1111/j.1742-1241.2009.02001.x. [78] M.V. Seeman, Psychopathology in women and men: focus on female hormones, Am. J. Psychiatry 154 (1997) 1641–1647. http://dx.doi.org/10.1176/ajp.154.12.1641. [79] P.A. McDermott, A nationwide study of developmental and gender prevalence for psychopathology in childhood and adolescence, J. Abnorm. Child Psychol. 24 (1996) 53–66. http://dx.doi.org/10.1007/BF01448373. [80] S. Torgersen, E. Kringlen, V. Cramer, The prevalence of personality disorders in a community sample, Arch. Gen. Psychiatry 58 (2001) 590–596. http://dx.doi.org/ 10.1001/archpsyc.58.6.590. [81] D.M. Buss, T.K. Shackelford, Human aggression in evolutionary psychological perspective, Clin. Psychol. Rev. 17 (1997) 605–619. http://dx.doi.org/10.1016/S02727358(97)00037-8. [82] J. Archer, Sex differences in aggression between heterosexual partners: a metaanalytic review, Psychol. Bull. 126 (2000) 651–680. http://dx.doi.org/10.1037/ 0033-2909.126.5.651. [83] J. Archer, Sex differences in aggression in real-world settings: a meta-analytic review, Rev. Gen. Psychol. 8 (2004) 291–322. http://dx.doi.org/10.1037/1089-2680.8.4.291. [84] J.E. Lansford, A.T. Skinner, E. Sorbring, L. Di Giunta, K. Deater-Deckard, K.A. Dodge, et al., Boys' and girls' relational and physical aggression in nine countries, Aggress. Behav. 38 (2012) 298–308. http://dx.doi.org/10.1002/ab.21433. [85] A. Campbell, The evolutionary psychology of women's aggression, Philos. Trans. R. Soc. B 368 (2013) 20130078. http://dx.doi.org/10.1098/rstb.2013.0078. [86] K. Österman, K. Björkqvist, K.M.J. Lagerspetz, A. Kaukiainen, S.F. Landau, A. Frączek, et al., Cross-cultural evidence of female indirect aggression, Aggress. Behav. 24 (1998) 1–8. http://dx.doi.org/10.1002/(SICI)1098-2337(1998)24:1b1::AID-AB1N3.0. CO;2-R. [87] K. Chichinadze, N. Chichinadze, A. Lazarashvili, Hormonal and neurochemical mechanisms of aggression and a new classification of aggressive behavior, Aggress. Violent Behav. 16 (2011) 461–471. http://dx.doi.org/10.1016/j.avb.2011.03.002. [88] K.M.J. Lagerspetz, K. Björkqvist, T. Peltonen, Is indirect aggression typical of females? Gender differences in aggressiveness in 11- to 12-year-old children, Aggress. Behav. 14 (1988) 403–414. http://dx.doi.org/10.1002/1098-2337(1988)14: 6b403::AID-AB2480140602N3.0.CO;2-D. [89] A. Kaukiainen, K. Björkqvist, K. Lagerspetz, K. Österman, C. Salmivalli, S. Rothberg, et al., The relationships between social intelligence, empathy, and three types of aggression, Aggress. Behav. 25 (1999) 81–89. http://dx.doi.org/10.1002/ (SICI)1098-2337(1999)25:2b81::AID-AB1N3.0.CO;2-M. [90] C. Salmivalli, A. Kaukiainen, K. Lagerspetz, Aggression and sociometric status among peers: do gender and type of aggression matter? Scand. J. Psychol. 41 (2000) 17–24. http://dx.doi.org/10.1111/1467-9450.00166. [91] T. Little, C. Henrich, S. Jones, P. Hawley, Disentangling the “whys” from the “whats” of aggressive behaviour, Int. J. Behav. Dev. 27 (2003) 122–133. http://dx.doi.org/ 10.1080/01650250244000128. [92] K. Björkqvist, Sex differences in physical, verbal, and indirect aggression: a review of recent research, Sex Roles 30 (1994) 177–188. http://dx.doi.org/10.1007/ BF01420988. [93] K. Björkqvist, K. Österman, K.M.J. Lagerspetz, Sex differences in covert aggression among adults, Aggress. Behav. 20 (1994) 27–33. http://dx.doi.org/10.1002/10982337(1994)20:1b27::AID-AB2480200105N3.0.CO;2-Q. [94] N.R. Crick, J.K. Grotpeter, Relational aggression, gender, and social–psychological adjustment, Child Dev. 66 (1995) 710–722. http://dx.doi.org/10.1111/j.14678624.1995.tb00900.x. [95] N.R. Crick, Engagement in gender normative versus nonnormative forms of aggression: links to social–psychological adjustment, Dev. Psychol. 33 (1997) 610–617. http://dx.doi.org/10.1037//0012-1649.33.4.610. [96] D.C. French, E.A. Jansen, S. Pidada, United States and Indonesian children's and adolescents' reports of relational aggression by disliked peers, Child Dev. 73 (2002) 1143–1150. http://dx.doi.org/10.1111/1467-8624.00463. [97] A.H. Eagly, V.J. Steffen, Gender and aggressive behavior: a meta-analytic review of the social psychological literature, Psychol. Bull. 100 (1986) 309–330. http://dx. doi.org/10.1037/0033-2909.100.3.309. [98] P. Lussier, R. Corrado, S. Tzoumakis, Gender differences in physical aggression and associated developmental correlates in a sample of Canadian preschoolers, Behav. Sci. Law 30 (2012) 643–671. http://dx.doi.org/10.1002/bsl.2035. [99] K. Björkqvist, K.M.J. Lagerspetz, A. Kaukiainen, Do girls manipulate and boys fight? Developmental trends in regard to direct and indirect aggression, Aggress. Behav. 18 (1992) 117–127. http://dx.doi.org/10.1002/1098-2337(1992)18:2b117::AIDAB2480180205N3.0.CO;2-3. [100] D.A. Hines, K.J. Saudino, Gender differences in psychological, physical, and sexual aggression among college students using the revised conflict tactics scales, Violence Vict. 18 (2003) 197–217. http://dx.doi.org/10.1891/vivi.2003.18.2.197.

131

[101] N.A. Card, B.D. Stucky, G.M. Sawalani, T.D. Little, Direct and indirect aggression during childhood and adolescence: a meta-analytic review of gender differences, intercorrelations, and relations to maladjustment, Child Dev. 79 (2008) 1185–1229. http://dx. doi.org/10.1111/j.1467-8624.2008.01184.x. [102] N.R. Crick, The role of overt aggression, relational aggression, and prosocial behavior in the prediction of children's future social adjustment, Child Dev. 67 (1996) 2317–2327. http://dx.doi.org/10.1111/j.1467-8624.1996.tb01859.x. [103] B.J. Leadbeater, E.M. Boone, N.A. Sangster, L.C. Mathieson, Sex differences in the personal costs and benefits of relational and physical aggression in high school, Aggress. Behav. 32 (2006) 409–419. http://dx.doi.org/10.1002/ab. 20139. [104] D.F. Hay, A. Nash, M. Caplan, J. Swartzentruber, F. Ishikawa, J.E. Vespo, The emergence of gender differences in physical aggression in the context of conflict between young peers, Br. J. Dev. Psychol. 29 (2011) 158–175. http://dx.doi.org/10. 1111/j.2044-835X.2011.02028.x. [105] M. Wallenius, R.-L. Punamäki, Digital game violence and direct aggression in adolescence: a longitudinal study of the roles of sex, age, and parent–child communication, J. Appl. Dev. Psychol. 29 (2008) 286–294. http://dx.doi.org/10.1016/j. appdev.2008.04.010. [106] J.M. Ramírez, J.M. Andreu, Aggression, and some related psychological constructs (anger, hostility, and impulsivity): some comments from a research project, Neurosci. Biobehav. Rev. 30 (2006) 276–291. http://dx.doi.org/10.1016/j. neubiorev.2005.04.015. [107] R.J.R. Blair, K.S. Peschardt, S. Budhani, D.G.V. Mitchell, D.S. Pine, The development of psychopathy, J. Child Psychol. Psychiatry 47 (2006) 262–276. http://dx.doi.org/10. 1111/j.1469-7610.2006.01596.x. [108] F. Poulin, M. Boivin, Reactive and proactive aggression: evidence of a two-factor model, Psychol. Assess. 12 (2000) 115–122. http://dx.doi.org/10.1037//1040-3590. 12.2.115. [109] R.J. Nelson, B.C. Trainor, Neural mechanisms of aggression, Nat. Rev. Neurosci. 8 (2007) 536–546. http://dx.doi.org/10.1038/nrn2174. [110] A. Siegel, J. Victoroff, Understanding human aggression: new insights from neuroscience, Int. J. Law Psychiatry 32 (2009) 209–215. http://dx.doi.org/10.1016/j.ijlp.2009. 06.001. [111] K.A. Dodge, J.D. Coie, Social-information-processing factors in reactive and proactive aggression in children's peer groups, J. Pers. Soc. Psychol. 53 (1987) 1146–1158. http://dx.doi.org/10.1037/0022-3514.53.6.1146. [112] E.S. Barratt, M.S. Stanford, T.A. Kent, A. Felthous, Neuropsychological and cognitive psychophysiological substrates of impulsive aggression, Biol. Psychiatry 41 (1997) 1045–1061. http://dx.doi.org/10.1016/S0006-3223(96)00175-8. [113] C.M. Pawliczek, B. Derntl, T. Kellermann, N. Kohn, R.C. Gur, U. Habel, Inhibitory control and trait aggression: neural and behavioral insights using the emotional stop signal task, Neuroimage 79 (2013) 264–274. http://dx.doi.org/10.1016/j. neuroimage.2013.04.104. [114] B.O. de Castro, J.W. Veerman, W. Koops, J.D. Bosch, H.J. Monshouwer, Hostile attribution of intent and aggressive behavior: a meta-analysis, Child Dev. 73 (2002) 916–934. http://dx.doi.org/10.1111/1467-8624.00447. [115] D. Seo, C.J. Patrick, P.J. Kennealy, Role of serotonin and dopamine system interactions in the neurobiology of impulsive aggression and its comorbidity with other clinical disorders, Aggress. Violent Behav. 13 (2008) 383–395. http://dx.doi.org/ 10.1016/j.avb.2008.06.003. [116] E.F. Coccaro, L.J. Siever, H.M. Klar, G. Maurer, K. Cochrane, T.B. Cooper, et al., Serotonergic studies in patients with affective and personality disorders. Correlates with suicidal and impulsive aggressive behavior, Arch. Gen. Psychiatry 46 (1989) 587–599. http://dx.doi.org/10.1001/archpsyc.1989.01810070013002. [117] L.J. Siever, Neurobiology of aggression and violence, Am. J. Psychiatry 165 (2008) 429–442. http://dx.doi.org/10.1176/appi.ajp.2008.07111774. [118] A.L. Glenn, A. Raine, Psychopathy and instrumental aggression: evolutionary, neurobiological, and legal perspectives, Int. J. Law Psychiatry 32 (2009) 253–258. http://dx.doi.org/10.1016/j.ijlp.2009.04.002. [119] A. Raine, J.R. Meloy, S. Bihrle, J. Stoddard, L. LaCasse, M.S. Buchsbaum, Reduced prefrontal and increased subcortical brain functioning assessed using positron emission tomography in predatory and affective murderers, Behav. Sci. Law 16 (1998) 319–332. http://dx.doi.org/10.1002/(sici)1099-0798(199822)16:3b319:: aid-bsl311N3.0.co;2-g. [120] D.E. Reidy, A. Zeichner, J.D. Miller, M.A. Martinez, Psychopathy and aggression: examining the role of psychopathy factors in predicting laboratory aggression under hostile and instrumental conditions, J. Res. Pers. 41 (2007) 1244–1251. http://dx. doi.org/10.1016/j.jrp.2007.03.001. [121] E.S. Barratt, M.S. Stanford, L. Dowdy, M.J. Liebman, T.A. Kent, Impulsive and premeditated aggression: a factor analysis of self-reported acts, Psychiatry Res. 86 (1999) 163–173. http://dx.doi.org/10.1016/s0165-1781(99)00024-4. [122] R.J.R. Blair, Neurobiological basis of psychopathy, Br. J. Psychiatry 182 (2003) 5–7. http://dx.doi.org/10.1192/bjp.182.1.5. [123] F. Vitaro, P.L. Gendreau, R.E. Tremblay, P. Oligny, Reactive and proactive aggression differentially predict later conduct problems, J. Child Psychol. Psychiatry 39 (1998) 377–385. http://dx.doi.org/10.1017/S0021963097002102. [124] R.J.R. Blair, The amygdala and ventromedial prefrontal cortex in morality and psychopathy, Trends Cogn. Sci. 11 (2007) 387–392. http://dx.doi.org/10.1016/j.tics.2007.07. 003. [125] D.F. Connor, R.J. Steingard, J.J. Anderson, R.H. Melloni, Gender differences in reactive and proactive aggression, Child Psychiatry Hum. Dev. 33 (2003) 279–294. http://dx.doi.org/10.1023/A:1023084112561. [126] G.A. van Wingen, L. Ossewaarde, T. Bäckström, E.J. Hermans, G. Fernández, Gonadal hormone regulation of the emotion circuitry in humans, Neuroscience 191 (2011) 38–45. http://dx.doi.org/10.1016/j.neuroscience.2011.04.042.

132


[127] E. Cashdan, Hormones and competitive aggression in women, Aggress. Behav. 29 (2003) 107–115. http://dx.doi.org/10.1002/ab.10041. [128] A.A. Bailey, P.L. Hurd, Finger length ratio (2D:4D) correlates with physical aggression in men but not in women, Biol. Psychol. 68 (2005) 215–222. http://dx.doi.org/ 10.1016/j.biopsycho.2004.05.001. [129] K.K. Soma, M.-A.L. Scotti, A.E.M. Newman, T.D. Charlier, G.E. Demas, Novel mechanisms for neuroendocrine regulation of aggression, Front. Neuroendocrinol. 29 (2008) 476–489. http://dx.doi.org/10.1016/j.yfrne.2007.12.003. [130] J.M. Ramirez, Hormones and aggression in childhood and adolescence, Aggress. Violent Behav. 8 (2003) 621–644. http://dx.doi.org/10.1016/S1359-1789(02)00102-7. [131] M. Giammanco, G. Tabacchi, S. Giammanco, D. Di Majo, M. La Guardia, Testosterone and aggressiveness, Med. Sci. Monit. 11 (2005) RA136–RA145 (http://www.ncbi. nlm.nih.gov/pubmed/15795710). [132] J. Archer, The influence of testosterone on human aggression, Br. J. Psychol. 82 (1991) 1–28. http://dx.doi.org/10.1111/j.2044-8295.1991.tb02379.x. [133] M. Berman, B. Gladue, S. Taylor, The effects of hormones, Type A behavior pattern, and provocation on aggression in men, Motiv. Emot. 17 (1993) 125–138. http://dx. doi.org/10.1007/BF00995189. [134] E. Pascual-Sagastizabal, A. Azurmendi, F. Braza, A.I. Vergara, J. Cardas, J.R. SánchezMartín, Parenting styles and hormone levels as predictors of physical and indirect aggression in boys and girls, Aggress. Behav. (2014)http://dx.doi.org/10.1002/ab. 21539 (Article first published online). [135] S.A. Berenbaum, S.M. Resnick, Early androgen effects on aggression in children and adults with congenital adrenal hyperplasia, Psychoneuroendocrinology 22 (1997) 505–515. http://dx.doi.org/10.1016/S0306-4530(97)00049-8. [136] C.C.C. Cohen-Bendahan, J.K. Buitelaar, S.H.M. van Goozen, J.F. Orlebeke, P.T. CohenKettenis, Is there an effect of prenatal testosterone on aggression and other behavioral traits? A study comparing same-sex and opposite-sex twin girls, Horm. Behav. 47 (2005) 230–237. http://dx.doi.org/10.1016/j.yhbeh.2004.10.006. [137] T.J. Shors, G. Miesegaes, Testosterone in utero and at birth dictates how stressful experience will affect learning in adulthood, Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 13955–13960. http://dx.doi.org/10.1073/pnas.202199999. [138] Z. Benderlioglu, R.J. Nelson, Digit length ratios predict reactive aggression in women, but not in men, Horm. Behav. 46 (2004) 558–564. http://dx.doi.org/10. 1016/j.yhbeh.2004.06.004. [139] H.G. Pope, E.M. Kouri, J.I. Hudson, Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial, Arch. Gen. Psychiatry 57 (2000) 133–140. http://dx.doi.org/10.1001/archpsyc.57.2.133. [140] P.J. Perry, E.C. Kutscher, B.C. Lund, W.R. Yates, T.L. Holman, L. Demers, Measures of aggression and mood changes in male weightlifters with and without androgenic anabolic steroid use, J. Forensic Sci. 48 (2003) 646–651 (http://www.ncbi.nlm. nih.gov/pubmed/12762541). [141] E.M. Kouri, S.E. Lukas, H.G. Pope, P.S. Oliva, Increased aggressive responding in male volunteers following the administration of gradually increasing doses of testosterone cypionate, Drug Alcohol Depend. 40 (1995) 73–79. http://dx.doi.org/10. 1016/0376-8716(95)01192-7. [142] A.S. Clark, L.P. Henderson, Behavioral and physiological responses to anabolicandrogenic steroids, Neurosci. Biobehav. Rev. 27 (2003) 413–436. http://dx.doi. org/10.1016/S0149-7634(03)00064-2. [143] J.M. Bjork, F.G. Moeller, D.M. Dougherty, A.C. Swann, Endogenous plasma testosterone levels and commission errors in women: a preliminary report, Physiol. Behav. 73 (2001) 217–221. http://dx.doi.org/10.1016/s0031-9384(01)00474-7. [144] T. Hildebrandt, J.W. Langenbucher, A. Flores, S. Harty, H. Berlin, The influence of age of onset and acute anabolic steroid exposure on cognitive performance, impulsivity, and aggression in men, Psychol. Addict. Behav. (2014)http://dx.doi.org/10. 1037/a0036482 (Advance online publication). [145] E.J. Hermans, N.F. Ramsey, J. van Honk, Exogenous testosterone enhances responsiveness to social threat in the neural circuitry of social aggression in humans, Biol. Psychiatry 63 (2008) 263–270. http://dx.doi.org/10.1016/j.biopsych.2007.05.013. [146] B. Derntl, C. Windischberger, S. Robinson, I. Kryspin-Exner, R.C. Gur, E. Moser, et al., Amygdala activity to fear and anger in healthy young males is associated with testosterone, Psychoneuroendocrinology 34 (2009) 687–693. http://dx.doi.org/10. 1016/j.psyneuen.2008.11.007. [147] S.J. Stanton, M.M. Wirth, C.E. Waugh, O.C. Schultheiss, Endogenous testosterone levels are associated with amygdala and ventromedial prefrontal cortex responses to anger faces in men but not women, Biol. Psychol. 81 (2009) 118–122. http://dx. doi.org/10.1016/j.biopsycho.2009.03.004. [148] C.K. Peterson, E. Harmon-Jones, Anger and testosterone: evidence that situationallyinduced anger relates to situationally-induced testosterone, Emotion 12 (2012) 899–902. http://dx.doi.org/10.1037/a0025300. [149] M.M. Wirth, O.C. Schultheiss, Basal testosterone moderates responses to anger faces in humans, Physiol. Behav. 90 (2007) 496–505. http://dx.doi.org/10.1016/j. physbeh.2006.10.016. [150] E.F. Coccaro, B. Beresford, P. Minar, J. Kaskow, T. Geracioti, CSF testosterone: relationship to aggression, impulsivity, and venturesomeness in adult males with personality disorder, J. Psychiatr. Res. 41 (2007) 488–492. http://dx.doi.org/10.1016/j. jpsychires.2006.04.009. [151] O.C. Schultheiss, M.M. Wirth, C.M. Torges, J.S. Pang, M.A. Villacorta, K.M. Welsh, Effects of implicit power motivation on men's and women's implicit learning and testosterone changes after social victory or defeat, J. Pers. Soc. Psychol. 88 (2005) 174–188. http://dx.doi.org/10.1037/0022-3514.88.1.174. [152] V.J. Grant, J.T. France, Dominance and testosterone in women, Biol. Psychol. 58 (2001) 41–47. http://dx.doi.org/10.1016/s0301-0511(01)00100-4. [153] P.H. Mehta, R.A. Josephs, Testosterone change after losing predicts the decision to compete again, Horm. Behav. 50 (2006) 684–692. http://dx.doi.org/10.1016/j. yhbeh.2006.07.001.

[154] P.C. Bernhardt, J.M. Dabbs, J.A. Fielden, C.D. Lutter, Testosterone changes during vicarious experiences of winning and losing among fans at sporting events, Physiol. Behav. 65 (1998) 59–62. http://dx.doi.org/10.1016/s00319384(98)00147-4. [155] S. Zilioli, N.V. Watson, Testosterone across successive competitions: evidence for a “winner effect” in humans? Psychoneuroendocrinology 47 (2014) 1–9. http://dx. doi.org/10.1016/j.psyneuen.2014.05.001. [156] J.M. Carré, S.K. Putnam, C.M. McCormick, Testosterone responses to competition predict future aggressive behaviour at a cost to reward in men, Psychoneuroendocrinology 34 (2009) 561–570. http://dx.doi.org/10.1016/ j.psyneuen.2008.10.018. [157] C. Eisenegger, J. Haushofer, E. Fehr, The role of testosterone in social interaction, Trends Cogn. Sci. 15 (2011) 263–271. http://dx.doi.org/10.1016/j.tics.2011.04.008. [158] A.S. Book, K.B. Starzyk, V.L. Quinsey, The relationship between testosterone and aggression: a meta-analysis, Aggress. Violent Behav. 6 (2001) 579–599. http://dx.doi. org/10.1016/S1359-1789(00)00032-X. [159] D. Terburg, B. Morgan, J. van Honk, The testosterone–cortisol ratio: a hormonal marker for proneness to social aggression, Int. J. Law Psychiatry 32 (2009) 216–223. http://dx.doi.org/10.1016/j.ijlp.2009.04.008. [160] A. Popma, R. Vermeiren, C.A.M.L. Geluk, T. Rinne, W. van den Brink, D.L. Knol, et al., Cortisol moderates the relationship between testosterone and aggression in delinquent male adolescents, Biol. Psychiatry 61 (2007) 405–411. http://dx.doi.org/10. 1016/j.biopsych.2006.06.006. [161] B.S. McEwen, Physiology and neurobiology of stress and adaptation: central role of the brain, Physiol. Rev. 87 (2007) 873–904. http://dx.doi.org/10.1152/physrev. 00041.2006. [162] E. Charmandari, C. Tsigos, G. Chrousos, Endocrinology of the stress response, Annu. Rev. Physiol. 67 (2005) 259–284. http://dx.doi.org/10.1146/annurev.physiol.67. 040403.120816. [163] K. McBurnett, B.B. Lahey, P.J. Rathouz, R. Loeber, Low salivary cortisol and persistent aggression in boys referred for disruptive behavior, Arch. Gen. Psychiatry 57 (2000) 38–43. http://dx.doi.org/10.1001/archpsyc.57.1.38. [164] M. Cima, T. Smeets, M. Jelicic, Self-reported trauma, cortisol levels, and aggression in psychopathic and non-psychopathic prison inmates, Biol. Psychol. 78 (2008) 75–86. http://dx.doi.org/10.1016/j.biopsycho.2007.12.011. [165] M.M. Johnson, K.M. Caron, A.J. Mikolajewski, E.A. Shirtcliff, L.A. Eckel, J. Taylor, Psychopathic traits, empathy, and aggression are differentially related to cortisol awakening response, J. Psychopathol. Behav. Assess. 36 (2014) 380–388. http:// dx.doi.org/10.1007/s10862-014-9412-7. [166] M.M. O'Leary, B.R. Loney, L.A. Eckel, Gender differences in the association between psychopathic personality traits and cortisol response to induced stress, Psychoneuroendocrinology 32 (2007) 183–191. http://dx.doi.org/ 10.1016/j.psyneuen.2006.12.004. [167] M.M. O'Leary, J. Taylor, L. Eckel, Psychopathic personality traits and cortisol response to stress: the role of sex, type of stressor, and menstrual phase, Horm. Behav. 58 (2010) 250–256. http://dx.doi.org/10.1016/j.yhbeh.2010.03.009. [168] P.H. Mehta, A.C. Jones, R.A. Josephs, The social endocrinology of dominance: basal testosterone predicts cortisol changes and behavior following victory and defeat, J. Pers. Soc. Psychol. 94 (2008) 1078–1093. http://dx.doi.org/10.1037/0022-3514. 94.6.1078. [169] S.H.M. van Goozen, G. Fairchild, H. Snoek, G.T. Harold, The evidence for a neurobiological model of childhood antisocial behavior, Psychol. Bull. 133 (2007) 149–182. http://dx.doi.org/10.1037/0033-2909.133.1.149. [170] K.K. Soma, N.M. Rendon, R. Boonstra, H.E. Albers, G.E. Demas, DHEA effects on brain and behavior: insights from comparative studies of aggression, J. Steroid Biochem. Mol. Biol. 145 (2014) 261–272. http://dx.doi.org/10.1016/j.jsbmb.2014.05.011. [171] D.H. Barzman, D. Mossman, K. Appel, T.J. Blom, J.R. Strawn, N.N. Ekhator, et al., The association between salivary hormone levels and children's inpatient aggression: a pilot study, Psychiatr. Q. 84 (2013) 475–484. http://dx.doi.org/10.1007/s11126013-9260-8. [172] S.H. van Goozen, W. Matthys, P.T. Cohen-Kettenis, J.H. Thijssen, H. van Engeland, Adrenal androgens and aggression in conduct disorder prepubertal boys and normal controls, Biol. Psychiatry 43 (1998) 156–158. http://dx.doi.org/10.1016/ S0006-3223(98)00360-6. [173] V.A. Gavrilova, S.A. Ivanova, S.I. Gusev, M.V. Trofimova, N.A. Bokhan, Neurosteroids dehydroepiandrosterone and its sulfate in individuals with personality disorders convicted of serious violent crimes, Bull. Exp. Biol. Med. 154 (2012) 89–91. http://dx.doi.org/10.1007/s10517-012-1882-6. [174] D.H. Barzman, A. Patel, L. Sonnier, J.R. Strawn, Neuroendocrine aspects of pediatric aggression: can hormone measures be clinically useful? Neuropsychiatr. Dis. Treat. 6 (2010) 691–697. http://dx.doi.org/10.2147/NDT.S5832. [175] K. Pajer, R. Tabbah, W. Gardner, R.T. Rubin, R.K. Czambel, Y. Wang, Adrenal androgen and gonadal hormone levels in adolescent girls with conduct disorder, Psychoneuroendocrinology 31 (2006) 1245–1256. http://dx.doi.org/10.1016/j. psyneuen.2006.09.005. [176] G.E. Abraham, Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle, J. Clin. Endocrinol. Metab. 39 (1974) 340–346. http://dx.doi. org/10.1097/00006254-197503000-00016. [177] C. Kirschbaum, B.M. Kudielka, J. Gaab, N.C. Schommer, D.H. Hellhammer, Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus–pituitary–adrenal axis, Psychosom. Med. 61 (1999) 154–162. http://dx. doi.org/10.1097/00006842-199903000-00006. [178] C.A. Roca, P.J. Schmidt, M. Altemus, P. Deuster, M.A. Danaceau, K. Putnam, et al., Differential menstrual cycle regulation of hypothalamic–pituitary–adrenal axis in women with premenstrual syndrome and controls, J. Clin. Endocrinol. Metab. 88 (2003) 3057–3063. http://dx.doi.org/10.1210/jc.2002-021570.

R.M.M. de Almeida et al. / Physiology & Behavior 143 (2015) 121–135 [179] L. Ossewaarde, E.J. Hermans, G.A. van Wingen, S.C. Kooijman, I.-M. Johansson, T. Bäckström, et al., Neural mechanisms underlying changes in stress-sensitivity across the menstrual cycle, Psychoneuroendocrinology 35 (2010) 47–55. http:// dx.doi.org/10.1016/j.psyneuen.2009.08.011. [180] I. Sundström Poromaa, S. Smith, M. Gulinello, GABA receptors, progesterone and premenstrual dysphoric disorder, Arch. Womens Ment. Health 6 (2003) 23–41. http://dx.doi.org/10.1007/s00737-002-0147-1. [181] R.R. Thompson, K. George, J.C. Walton, S.P. Orr, J. Benson, Sex-specific influences of vasopressin on human social communication, Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 7889–7894. http://dx.doi.org/10.1073/pnas.0600406103. [182] C.F. Ferris, Y. Delville, Vasopressin and serotonin interactions in the control of agonistic behavior, Psychoneuroendocrinology 19 (1994) 593–601. http://dx.doi.org/ 10.1016/0306-4530(94)90043-4. [183] H.E. Albers, The regulation of social recognition, social communication and aggression: vasopressin in the social behavior neural network, Horm. Behav. 61 (2012) 283–292. http://dx.doi.org/10.1016/j.yhbeh.2011.10.007. [184] A. Fodor, B. Barsvari, M. Aliczki, Z. Balogh, D. Zelena, S.R. Goldberg, et al., The effects of vasopressin deficiency on aggression and impulsiveness in male and female rats, Psychoneuroendocrinology 47 (2014) 141–150. http://dx.doi.org/10.1016/j. psyneuen.2014.05.010. [185] E.F. Coccaro, M. Kavoussi, R.L. Hauger, T.B. Cooper, C.F. Ferris, Cerebrospinal fluid vasopressin levels, Arch. Gen. Psychiatry 55 (1998) 3–7. http://dx.doi.org/10. 1001/archpsyc.55.8.708. [186] D. Luppino, C. Moul, D.J. Hawes, J. Brennan, M.R. Dadds, Association between a polymorphism of the vasopressin 1B receptor gene and aggression in children, Psychiatr. Genet. 24 (2014) 185–190. http://dx.doi.org/10.1097/YPG.00000000000000366. [187] H.E. Albers, Species, sex and individual differences in the vasotocin/vasopressin system: relationship to neurochemical signaling in the social behavior neural network, Front. Neuroendocrinol. (2014)http://dx.doi.org/10.1016/j.yfrne.2014.07. 001. [188] L. van Londen, J.G. Goekoop, G.M. van Kempen, A.C. Frankhuijzen-Sierevogel, V.M. Wiegant, E.A. van der Velde, et al., Plasma levels of arginine vasopressin elevated in patients with major depression, Neuropsychopharmacology 17 (1997) 284–292. http://dx.doi.org/10.1016/S0893-133X(97)00054-7. [189] A.E. Johnson, C. Barberis, H.E. Albers, Castration reduces vasopressin receptor binding in the hamster hypothalamus, Brain Res. 674 (1995) 153–158. http://dx.doi. org/10.1016/0006-8993(95)00010-N. [190] P.A. Bos, J. Panksepp, R.M. Bluthé, J. Van Honk, Acute effects of steroid hormones and neuropeptides on human social–emotional behavior: a review of single administration studies, Front. Neuroendocrinol. 33 (2012) 17–35. http://dx.doi.org/ 10.1016/j.yfrne.2011.01.002. [191] Y. Delville, K.M. Mansour, C.F. Ferris, Testosterone facilitates aggression by modulating vasopressin receptors in the hypothalamus, Physiol. Behav. 60 (1996) 25–29. http://dx.doi.org/10.1016/0031-9384(95)02246-5. [192] A.M. Bao, G. Meynen, D.F. Swaab, The stress system in depression and neurodegeneration: focus on the human hypothalamus, Brain Res. Rev. 57 (2008) 531–553. http://dx.doi.org/10.1016/j.brainresrev.2007.04.005. [193] L.V. Scott, T.G. Dinan, Vasopressin and the regulation of hypothalamic–pituitary– adrenal axis function: implications for the pathophysiology of depression, Life Sci. 62 (1998) 1985–1998. http://dx.doi.org/10.1016/S0024-3205(98)00027-7. [194] J.K. Kim, S.N. Summer, W.M. Wood, R.W. Schrier, Role of glucocorticoid hormones in arginine vasopressin gene regulation, Biochem. Biophys. Res. Commun. 289 (2001) 1252–1256. http://dx.doi.org/10.1006/bbrc.2001.6114. [195] H. Damasio, T. Grabowski, R. Frank, A. Galaburda, A. Damasio, The return of Phineas Gage: clues about the brain from the skull of a famous patient, Science 264 (1994) 1102–1105. http://dx.doi.org/10.1126/science.8178168 (80-.). [196] R.J. Davidson, K.M. Putnam, C.L. Larson, Dysfunction in the neural circuitry of emotion regulation: a possible prelude to violence, Science 289 (2000) 591–594. http://dx.doi.org/10.1126/science.289.5479.591 (80-.). [197] S.W. Anderson, A. Bechara, H. Damasio, D. Tranel, A.R. Damasio, Impairment of social and moral behavior related to early damage in human prefrontal cortex, Nat. Neurosci. 2 (1999) 1032–1037. http://dx.doi.org/10.1038/14833. [198] E.K. Miller, J.D. Cohen, An integrative theory of prefrontal cortex function, Annu. Rev. Neurosci. 24 (2001) 167–202. http://dx.doi.org/10.1146/annurev.neuro.24.1. 167. [199] J. Grafman, K. Schwab, D. Warden, A. Pridgen, H.R. Brown, A.M. Salazar, Frontal lobe injuries, violence, and aggression: a report of the Vietnam Head Injury Study, Neurology 46 (1996) 1231-1231. http://dx.doi.org/10.1212/WNL.46.5.1231. [200] M.L. Kringelbach, E.T. Rolls, The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology, Prog. Neurobiol. 72 (2004) 341–372. http://dx.doi.org/10.1016/j.pneurobio.2004.03. 006. [201] A. Raine, T. Lencz, S. Bihrle, L. LaCasse, P. Colletti, Reduced prefrontal gray matter volume and reduced autonomic activity in antisocial personality disorder, Arch. Gen. Psychiatry 57 (2000) 119–129. http://dx.doi.org/10.1001/archpsyc.57.2.119. [202] N. Birbaumer, R. Veit, M. Lotze, M. Erb, C. Hermann, W. Grodd, et al., Deficient fear conditioning in psychopathy: a functional magnetic resonance imaging study, Arch. Gen. Psychiatry 62 (2005) 799–805. http://dx.doi.org/10.1001/archpsyc.62. 7.799. [203] J. Tiihonen, R. Rossi, M.P. Laakso, S. Hodgins, C. Testa, J. Perez, et al., Brain anatomy of persistent violent offenders: more rather than less, Psychiatry Res. 163 (2008) 201–212. http://dx.doi.org/10.1016/j.pscychresns.2007.08.012. [204] V.M. Narayan, K.L. Narr, V. Kumari, R.P. Woods, P.M. Thompson, A.W. Toga, et al., Regional cortical thinning in subjects with violent antisocial personality disorder or schizophrenia, Am. J. Psychiatry 164 (2007) 1418–1427. http://dx.doi.org/10. 1176/appi.ajp.2007.06101631.

133

[205] P.F. Goyer, P.J. Andreason, W.E. Semple, A.H. Clayton, A.C. King, B.A. Compton-Toth, et al., Positron-emission tomography and personality disorders, Neuropsychopharmacology 10 (1994) 21–28. http://dx.doi.org/10. 1038/npp.1994.3. [206] A.S. New, E.A. Hazlett, M.S. Buchsbaum, M. Goodman, S.A. Mitelman, R. Newmark, et al., Amygdala–prefrontal disconnection in borderline personality disorder, Neuropsychopharmacology 32 (2007) 1629–1640. http://dx.doi.org/10.1038/sj. npp.1301283. [207] P.H. Mehta, J. Beer, Neural mechanisms of the testosterone-aggression relation: the role of orbitofrontal cortex, J. Cogn. Neurosci. 22 (2009) 2357–2368. http://dx.doi. org/10.1162/jocn.2009.21389. [208] S.L. Crowe, R.J.R. Blair, The development of antisocial behavior: what can we learn from functional neuroimaging studies? Dev. Psychopathol. 20 (2008) 1145–1159. http://dx.doi.org/10.1017/S0954579408000540. [209] P. Pietrini, M. Guazzelli, G. Basso, K. Jaffe, J. Grafman, Neural correlates of imaginal aggressive behavior assessed by positron emission tomography in healthy subjects, Am. J. Psychiatry 157 (2000) 1772–1781. http://dx.doi.org/10.1176/appi. ajp.157.11.1772. [210] P.H. Soloff, C.C. Meltzer, C. Becker, P.J. Greer, T.M. Kelly, D. Constantine, Impulsivity and prefrontal hypometabolism in borderline personality disorder, Psychiatry Res. Neuroimaging 123 (2003) 153–163. http://dx.doi.org/10.1016/S0925-4927(03)00064-7. [211] N.D. Volkow, L.R. Tancredi, C. Grant, H. Gillespie, A. Valentine, N. Mullani, et al., Brain glucose metabolism in violent psychiatric patients: a preliminary study, Psychiatry Res. 61 (1995) 243–253. http://dx.doi.org/10.1016/0925-4927(95)02671-j. [212] S. Ducharme, J.J. Hudziak, K.N. Botteron, H. Ganjavi, C. Lepage, D.L. Collins, et al., Right anterior cingulate cortical thickness and bilateral striatal volume correlate with child behavior checklist aggressive behavior scores in healthy children, Biol. Psychiatry 70 (2011) 283–290. http://dx.doi.org/10.1016/j.biopsych.2011.03.015. [213] L. Young, A. Bechara, D. Tranel, H. Damasio, M. Hauser, A. Damasio, Damage to ventromedial prefrontal cortex impairs judgment of harmful intent, Neuron 65 (2010) 845–851. http://dx.doi.org/10.1016/j.neuron.2010.03.003. [214] P.A. Bos, E.J. Hermans, N.F. Ramsey, J. van Honk, The neural mechanisms by which testosterone acts on interpersonal trust, Neuroimage 61 (2012) 730–737. http:// dx.doi.org/10.1016/j.neuroimage.2012.04.002. [215] G.A. van Wingen, S.A. Zylicz, S. Pieters, C. Mattern, R.J. Verkes, J.K. Buitelaar, et al., Testosterone increases amygdala reactivity in middle-aged women to a young adulthood level, Neuropsychopharmacology 34 (2009) 539–547. http://dx.doi. org/10.1038/npp.2008.2. [216] G.A. van Wingen, C. Mattern, R.J. Verkes, J. Buitelaar, G. Fernández, Testosterone reduces amygdala–orbitofrontal cortex coupling, Psychoneuroendocrinology 35 (2010) 105–113. http://dx.doi.org/10.1016/j.psyneuen.2009.09.007. [217] S. Matthies, N. Rüsch, M. Weber, K. Lieb, A. Philipsen, O. Tuescher, et al., Small amygdala-high aggression? The role of the amygdala in modulating aggression in healthy subjects, World J. Biol. Psychiatry 13 (2012) 75–81. http://dx.doi.org/ 10.3109/15622975.2010.541282. [218] M. Davis, P.J. Whalen, The amygdala: vigilance and emotion, Mol. Psychiatry 6 (2001) 13–34. http://dx.doi.org/10.1038/sj.mp.4000812. [219] J.L. Price, Comparative aspects of amygdala connectivity, Ann. N. Y. Acad. Sci. 985 (2003) 50–58. http://dx.doi.org/10.1111/j.1749-6632.2003.tb07070.x. [220] L. Stefanacci, D.G. Amaral, Some observations on cortical inputs to the macaque monkey amygdala: an anterograde tracing study, J. Comp. Neurol. 451 (2002) 301–323. http://dx.doi.org/10.1002/cne.10339. [221] G.J. Quirk, J.S. Beer, Prefrontal involvement in the regulation of emotion: convergence of rat and human studies, Curr. Opin. Neurobiol. 16 (2006) 723–727. http://dx.doi.org/10.1016/j.conb.2006.07.004. [222] S.B. Manuck, A.L. Marsland, J.D. Flory, A. Gorka, R.E. Ferrell, A.R. Hariri, Salivary testosterone and a trinucleotide (CAG) length polymorphism in the androgen receptor gene predict amygdala reactivity in men, Psychoneuroendocrinology 35 (2010) 94–104. http://dx.doi.org/10.1016/j.psyneuen.2009.04.013. [223] M.J.A.G. Henckens, G.A. van Wingen, M. Joëls, G. Fernández, Time-dependent effects of corticosteroids on human amygdala processing, J. Neurosci. 30 (2010) 12725–12732. http://dx.doi.org/10.1523/JNEUROSCI. 3112-10.2010. [224] T. Hajszan, N.J. MacLusky, C. Leranth, Role of androgens and the androgen receptor in remodeling of spine synapses in limbic brain areas, Horm. Behav. 53 (2008) 638–646. http://dx.doi.org/10.1016/j.yhbeh.2007.12.007. [225] S. Sarkey, I. Azcoitia, L.M. Garcia-Segura, D. Garcia-Ovejero, L.L. DonCarlos, Classical androgen receptors in non-classical sites in the brain, Horm. Behav. 53 (2008) 753–764. http://dx.doi.org/10.1016/j.yhbeh.2008.02.015. [226] D.S. Reddy, K. Jian, The testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAA receptors, J. Pharmacol. Exp. Ther. 334 (2010) 1031–1041. http://dx.doi.org/10.1124/jpet.110.169854. [227] J.L. Aikey, J.G. Nyby, D.M. Anmuth, P.J. James, Testosterone rapidly reduces anxiety in male house mice (Mus musculus), Horm. Behav. 42 (2002) 448–460. http://dx. doi.org/10.1006/hbeh.2002.1838. [228] E. Lentini, M. Kasahara, S. Arver, I. Savic, Sex differences in the human brain and the impact of sex chromosomes and sex hormones, Cereb. Cortex 23 (2013) 2322–2336. http://dx.doi.org/10.1093/cercor/bhs222. [229] T.A.W. Visser, J.L. Ohan, S. Whittle, M. Yücel, J.G. Simmons, N.B. Allen, Sex differences in structural brain asymmetry predict overt aggression in early adolescents, Soc. Cogn. Affect. Neurosci. 9 (2014) 553–560. http://dx.doi.org/10.1093/scan/ nst013. [230] H. Liu, Y. Tang, F. Womer, G. Fan, T. Lu, N. Driesen, et al., Differentiating patterns of amygdala–frontal functional connectivity in schizophrenia and bipolar disorder, Schizophr. Bull. 40 (2014) 469–477. http://dx.doi.org/10.1093/schbul/sbt044. [231] C.A. Burghy, D.E. Stodola, P.L. Ruttle, E.K. Molloy, J.M. Armstrong, J.A. Oler, et al., Developmental pathways to amygdala–prefrontal function and internalizing

134

[232]

[233]

[234]

[235] [236]

[237]

[238]

[239]

[240]

[241]

[242]

[243]

[244]

[245]

[246]

[247]

[248]

[249]

[250]

[251]

[252]

[253]

[254]

[255]

[256]

R.M.M. de Almeida et al. / Physiology & Behavior 143 (2015) 121–135 symptoms in adolescence, Nat. Neurosci. 15 (2012) 1736–1741. http://dx.doi.org/ 10.1038/nn.3257. S.B. Perlman, J.R.C. Almeida, D.M. Kronhaus, A. Versace, E.J. Labarbara, C.R. Klein, et al., Amygdala activity and prefrontal cortex–amygdala effective connectivity to emerging emotional faces distinguish remitted and depressed mood states in bipolar disorder, Bipolar Disord. 14 (2012) 162–174. http://dx.doi.org/10.1111/j.13995618.2012.00999.x. R.J.R. Blair, Neuroimaging of psychopathy and antisocial behavior: a targeted review, Curr. Psychiatry Rep. 12 (2010) 76–82. http://dx.doi.org/10.1007/s11920009-0086-x. D.S. Reddy, Neurosteroids: endogenous role in the human brain and therapeutic potentials, Prog. Brain Res. 186 (2010) 113–137. http://dx.doi.org/10.1016/B9780-444-53630-3.00008-7. D. Belelli, J.J. Lambert, Neurosteroids: endogenous regulators of the GABA(A) receptor, Nat. Rev. Neurosci. 6 (2005) 565–575. http://dx.doi.org/10.1038/nrn1703. E.W. Fish, S. Faccidomo, J.F. DeBold, K.A. Miczek, Alcohol, allopregnanolone and aggression in mice, Psychopharmacology (Berl.) 153 (2001) 473–483. http://dx.doi. org/10.1007/s002130000587. D.R. Cherek, R. Spiga, M. Egli, Effects of response requirement and alcohol on human aggressive responding, J. Exp. Anal. Behav. 58 (1992) 577–587. http://dx. doi.org/10.1901/jeab. 1992.58-577. P.R. Giancola, The influence of trait anger on the alcohol-aggression relation in men and women, Alcohol. Clin. Exp. Res. 26 (2002) 1350–1358. http://dx.doi.org/10. 1097/01.ALC.0000030842.77279.C4. B.J. Bushman, H.M. Cooper, Effects of alcohol on human aggression: an integrative research review, Psychol. Bull. 107 (1990) 341–354. http://dx.doi.org/10.1037// 0033-2909.107.3.341. S.L. Gourley, J.F. Debold, W. Yin, J. Cook, K.A. Miczek, Benzodiazepines and heightened aggressive behavior in rats: reduction by GABA(A)/alpha(1) receptor antagonists, Psychopharmacology (Berl.) 178 (2005) 232–240. http://dx.doi.org/10. 1007/s00213-004-1987-3. D.D. Ben-Porath, S.P. Taylor, The effects of diazepam (valium) and aggressive disposition on human aggression: an experimental investigation, Addict. Behav. 27 (2002) 167–177. http://dx.doi.org/10.1016/s0306-4603(00)00175-1. R.M. McKernan, T.W. Rosahl, D.S. Reynolds, C. Sur, K.A. Wafford, J.R. Atack, et al., Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype, Nat. Neurosci. 3 (2000) 587–592. http://dx. doi.org/10.1038/75761. G.R. Dawson, N. Collinson, J.R. Atack, Development of subtype selective GABAA modulators, CNS Spectr. 10 (2005) 21–27 (http://www.ncbi.nlm.nih.gov/ pubmed/15618944, accessed August 09, 2014). D.A. Rund, J.D. Ewing, K. Mitzel, N. Votolato, The use of intramuscular benzodiazepines and antipsychotic agents in the treatment of acute agitation or violence in the emergency department, J. Emerg. Med. 31 (2006) 317–324. http://dx.doi.org/ 10.1016/j.jemermed.2005.09.021. B. Dell'osso, M. Lader, Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal, Eur. Psychiatry 28 (2013) 7–20. http://dx.doi.org/10.1016/j.eurpsy.2011.11.003. A.J. Bond, H.V. Curran, M.S. Bruce, G. O'Sullivan, P. Shine, Behavioural aggression in panic disorder after 8 weeks' treatment with alprazolam, J. Affect. Disord. 35 (1995) 117–123. http://dx.doi.org/10.1016/0165-0327(95)00053-4. G. Pinna, R.C. Agis-Balboa, F. Pibiri, M. Nelson, A. Guidotti, E. Costa, Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive behavior in mice, Neurochem. Res. 33 (2008) 1990–2007. http://dx.doi.org/10.1007/s11064-0089718-5. K.A. Miczek, E.W. Fish, J.F. De Bold, Neurosteroids, GABAA receptors, and escalated aggressive behavior, Horm. Behav. 44 (2003) 242–257. http://dx.doi.org/10.1016/j. yhbeh.2003.04.002. B. Segebladh, E. Bannbers, L. Moby, S. Nyberg, M. Bixo, T. Bäckström, et al., Allopregnanolone serum concentrations and diurnal cortisol secretion in women with premenstrual dysphoric disorder, Arch. Womens Ment. Health 16 (2013) 131–137. http://dx.doi.org/10.1007/s00737-013-0327-1. P. Monteleone, S. Luisi, A. Tonetti, F. Bernardi, A.D. Genazzani, M. Luisi, et al., Allopregnanolone concentrations and premenstrual syndrome, Eur. J. Endocrinol. 142 (2000) 269–273. http://dx.doi.org/10.1530/eje.0.1420269. S.S. Girdler, P.A. Straneva, K.C. Light, C.A. Pedersen, A.L. Morrow, Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder, Biol. Psychiatry 49 (2001) 788–797. http://dx.doi.org/10.1016/s0006-3223(00)01044-1. S. Nyberg, G. Wahlström, T. Bäckström, I. Sundström Poromaa, Altered sensitivity to alcohol in the late luteal phase among patients with premenstrual dysphoric disorder, Psychoneuroendocrinology 29 (2004) 767–777. http://dx.doi.org/10. 1016/S0306-4530(03)00121-5. I. Sundström, S. Nyberg, T. Bäckström, Patients with premenstrual syndrome have reduced sensitivity to midazolam compared to control subjects, Neuropsychopharmacology 17 (1997) 370–381. http://dx.doi.org/10.1016/ S0893-133X(97)00086-9. T. Bäckström, D. Haage, M. Löfgren, I.M. Johansson, J. Strömberg, S. Nyberg, et al., Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons, Neuroscience 191 (2011) 46–54. http:// dx.doi.org/10.1016/j.neuroscience.2011.03.061. E.W. Fish, J.F. DeBold, K.A. Miczek, Escalated aggression as a reward: corticosterone and GABA(A) receptor positive modulators in mice, Psychopharmacology (Berl.) 182 (2005) 116–127. http://dx.doi.org/10.1007/s00213-005-0064-x. J.D. Higley, P.T. Mehlman, R.E. Poland, D.M. Taub, J. Vickers, S.J. Suomi, et al., CSF testosterone and 5-HIAA correlate with different types of aggressive behaviors, Biol. Psychiatry 40 (1996) 1067–1082. http://dx.doi.org/10.1016/S0006-3223(95)00675-3.

[257] M. Virkkunen, R. Rawlings, R. Tokola, R.E. Poland, A. Guidotti, C. Nemeroff, et al., CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers, Arch. Gen. Psychiatry 51 (1994) 20–27. http://dx.doi.org/10.1001/archpsyc.1994.03950010020003. [258] P.H. Soloff, T.M. Kelly, S.J. Strotmeyer, K.M. Malone, J.J. Mann, Impulsivity, gender, and response to fenfluramine challenge in borderline personality disorder, Psychiatry Res. 119 (2003) 11–24. http://dx.doi.org/10.1016/S0165-1781(03)00100-8. [259] E.F. Coccaro, J.M. Silverman, H.M. Klar, T.B. Horvath, L.J. Siever, Familial correlates of reduced central serotonergic system function in patients with personality disorders, Arch. Gen. Psychiatry 51 (1994) 318–324. http://dx.doi.org/10.1001/ archpsyc.1994.03950040062008. [260] A.S. Unis, E.H. Cook, J.G. Vincent, D.K. Gjerde, B.D. Perry, C. Mason, et al., Platelet serotonin measures in adolescents with conduct disorder, Biol. Psychiatry 42 (1997) 553–559. http://dx.doi.org/10.1016/S0006-3223(96)00465-9. [261] C. Reist, K. Nakamura, E. Sagart, K.N. Sokolski, K.A. Fujimoto, Impulsive aggressive behavior: open-label treatment with citalopram, J. Clin. Psychiatry 64 (2003) 81–85. [262] E.F. Coccaro, R.J. Kavoussi, Fluoxetine and impulsive aggressive behavior in personality-disordered subjects, Arch. Gen. Psychiatry 54 (1997) 1081–1088. http://dx.doi.org/10.1001/archpsyc.1997.01830240035005. [263] A.S. New, M.S. Buchsbaum, E.A. Hazlett, M. Goodman, H.W. Koenigsberg, J. Lo, et al., Fluoxetine increases relative metabolic rate in prefrontal cortex in impulsive aggression, Psychopharmacology (Berl.) 176 (2004) 451–458. http://dx.doi.org/10. 1007/s00213-004-1913-8. [264] C. Spindelegger, R. Lanzenberger, W. Wadsak, L.K. Mien, P. Stein, M. Mitterhauser, et al., Influence of escitalopram treatment on 5-HT 1A receptor binding in limbic regions in patients with anxiety disorders, Mol. Psychiatry 14 (2009) 1040–1050. http://dx.doi.org/10.1038/mp.2008.35. [265] T.M. Moore, A. Scarpa, A. Raine, A meta-analysis of serotonin metabolite 5-HIAA and antisocial behavior, Aggress. Behav. 28 (2002) 299–316. http://dx.doi.org/10. 1002/ab.90027. [266] B.J. van der Vegt, N. Lieuwes, E.H.E.M. van de Wall, K. Kato, L. Moya-Albiol, S. Martínez-Sanchis, et al., Activation of serotonergic neurotransmission during the performance of aggressive behavior in rats, Behav. Neurosci. 117 (2003) 667–674. http://dx.doi.org/10.1037/0735-7044.117.4.667. [267] B. Olivier, R. van Oorschot, 5-HT1B receptors and aggression: a review, Eur. J. Pharmacol. 526 (2005) 207–217. http://dx.doi.org/10.1016/j.ejphar.2005.09.066. [268] M. Nomura, Y. Nomura, Psychological, neuroimaging, and biochemical studies on functional association between impulsive behavior and the 5-HT2A receptor gene polymorphism in humans, Ann. N. Y. Acad. Sci. 1086 (2006) 134–143. http://dx.doi.org/10.1196/annals.1377.004. [269] P.R. Albert, F. Vahid-Ansari, C. Luckhart, Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5HT1A receptor expression, Front. Behav. Neurosci. 8 (2014) 199. http://dx.doi. org/10.3389/fnbeh.2014.00199. [270] A.V. Witte, A. Flöel, P. Stein, M. Savli, L.-K. Mien, W. Wadsak, et al., Aggression is related to frontal serotonin-1A receptor distribution as revealed by PET in healthy subjects, Hum. Brain Mapp. 30 (2009) 2558–2570. http://dx.doi.org/10.1002/ hbm.20687. [271] L.J. Siever, M.S. Buchsbaum, A.S. New, J. Spiegel-Cohen, T. Wei, E.A. Hazlett, et al., d, l-Fenfluramine response in impulsive personality disorder assessed with [18F]fluorodeoxyglucose positron emission tomography, Neuropsychopharmacology 20 (1999) 413–423. http://dx.doi.org/10.1016/S0893-133X(98)00111-0. [272] P.H. Soloff, C.C. Meltzer, P.J. Greer, D. Constantine, T.M. Kelly, A fenfluramineactivated FDG-PET study of borderline personality disorder, Biol. Psychiatry 47 (2000) 540–547. http://dx.doi.org/10.1016/s0006-3223(99)00202-4. [273] A.S. New, E.A. Hazlett, M.S. Buchsbaum, M. Goodman, D. Reynolds, V. Mitropoulou, et al., Blunted prefrontal cortical 18Fluorodeoxyglucose positron emission tomography response to meta-chlorophenylpiperazine in impulsive aggression, Arch. Gen. Psychiatry 59 (2002) 621–629. http://dx.doi.org/10.1001/archpsyc.59.7.621. [274] W.G. Frankle, I. Lombardo, A.S. New, M. Goodman, P.S. Talbot, Y. Huang, et al., Brain serotonin transporter distribution in subjects with impulsive aggressivity: a positron emission study with [11C]McN 5652, Am. J. Psychiatry 162 (2005) 915–923. http://dx.doi.org/10.1176/appi.ajp.162.5.915. [275] T. Paus, Primate anterior cingulate cortex: where motor control, drive and cognition interface, Nat. Rev. Neurosci. 2 (2001) 417–424. http://dx.doi.org/10.1038/ 35077500. [276] A.V. Akhmadeev, L.B. Kalimullina, Sex steroids and monoamines in the system of neuroendocrine regulation of the functions of the amygdaloid complex of the brain, Neurosci. Behav. Physiol. 43 (2013) 129–134. http://dx.doi.org/10.1007/ s11055-012-9702-z. [277] G. Pinna, E. Costa, A. Guidotti, Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake, Psychopharmacology (Berl.) 186 (2006) 362–372. http://dx.doi.org/10. 1007/s00213-005-0213-2. [278] J. Hennig, M. Reuter, P. Netter, C. Burk, O. Landt, Two types of aggression are differentially related to serotonergic activity and the A779C TPH polymorphism, Behav. Neurosci. 119 (2005) 16–25. http://dx.doi.org/10.1037/0735-7044.119.1.16. [279] R. Miller, M. Wankerl, T. Stalder, C. Kirschbaum, N. Alexander, The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cortisol stress reactivity: a meta-analysis, Mol. Psychiatry 18 (2012) 1018–1024. http://dx.doi.org/10.1038/ mp.2012.124. [280] R.J. Porter, P. Gallagher, S. Watson, A.H. Young, Corticosteroid–serotonin interactions in depression: a review of the human evidence, Psychopharmacology (Berl.) 173 (2004) 1–17. http://dx.doi.org/10.1007/s00213-004-1774-1. [281] M. Almeida, R. Lee, E.F. Coccaro, Cortisol responses to ipsapirone challenge correlate with aggression, while basal cortisol levels correlate with impulsivity, in


[282] [283]

[284]

[285]

[286]

[287]

[288]

[289]

[290]

[291]

[292]

[293]

[294]

[295]

personality disorder and healthy volunteer subjects, J. Psychiatr. Res. 44 (2010) 874–880. http://dx.doi.org/10.1016/j.jpsychires.2010.02.012. P.J. Cowen, Cortisol, serotonin and depression: all stressed out? Br. J. Psychiatry 180 (2002) 99–100. http://dx.doi.org/10.1192/bjp.180.2.99. T.R. Morrison, R.H. Melloni, The role of serotonin, vasopressin, and serotonin/vasopressin interactions in aggressive behavior, in: K.A. Miczek, A. Meyer-Lindenberg (Eds.), Neurosci. Aggress. - Curr. Top. Behav. Neurosci, Springer Berlin Heidelberg, 2014, pp. 189–228. http://dx.doi.org/10.1007/7854_2014_283. Y. Delville, K.M. Mansour, C.F. Ferris, Serotonin blocks vasopressin-facilitated offensive aggression: interactions within the ventrolateral hypothalamus of golden hamsters, Physiol. Behav. 59 (1996) 813–816. http://dx.doi.org/10.1016/00319384(95)02166-3. D.F. Swaab, Sexual differentiation of the brain and behavior, Best Pract. Res. Clin. Endocrinol. Metab. 21 (2007) 431–444. http://dx.doi.org/10.1016/j.beem.2007. 04.003. J.W. Buckholtz, A. Meyer-Lindenberg, MAOA and the neurogenetic architecture of human aggression, Trends Neurosci. 31 (2008) 120–129. http://dx.doi.org/10. 1016/j.tins.2007.12.006. A. Caspi, J. McClay, T.E. Moffitt, J. Mill, J. Martin, I.W. Craig, et al., Role of genotype in the cycle of violence in maltreated children, Science 297 (2002) 851–854. http:// dx.doi.org/10.1126/science.1072290 (80-.). S.B. Manuck, J.D. Flory, R.E. Ferrell, J.J. Mann, M.F. Muldoon, A regulatory polymorphism of the monoamine oxidase-A gene may be associated with variability in aggression, impulsivity, and central nervous system serotonergic responsivity, Psychiatry Res. 95 (2000) 9–23. http://dx.doi.org/10.1016/s0165-1781(00)00162-1. C. Aslund, N. Nordquist, E. Comasco, J. Leppert, L. Oreland, K.W. Nilsson, Maltreatment, MAOA, and delinquency: sex differences in gene–environment interaction in a large population-based cohort of adolescents, Behav. Genet. 41 (2011) 262–372. http://dx.doi.org/10.1007/s10519-010-9356-y. A. Meyer-Lindenberg, J.W. Buckholtz, B. Kolachana, A.R. Hariri, L. Pezawas, G. Blasi, et al., Neural mechanisms of genetic risk for impulsivity and violence in humans, Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 6269–6274. http://dx.doi.org/10.1073/ pnas.0511311103. R. McDermott, D. Tingley, J. Cowden, G. Frazzetto, D.D.P. Johnson, Monoamine oxidase A gene (MAOA) predicts behavioral aggression following provocation, Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 2118–2123. http://dx.doi.org/10.1073/pnas. 0808376106. N.I. Eisenberger, B.M. Way, S.E. Taylor, W.T. Welch, M.D. Lieberman, Understanding genetic risk for aggression: clues from the brain's response to social exclusion, Biol. Psychiatry 61 (2007) 1100–1108. http://dx.doi.org/10.1016/j.biopsych.2006.08. 007. J. Kim-Cohen, A. Caspi, A. Taylor, B. Williams, R. Newcombe, I.W. Craig, et al., MAOA, maltreatment, and gene–environment interaction predicting children's mental health: new evidence and a meta-analysis, Mol. Psychiatry 11 (2006) 903–913. http://dx.doi.org/10.1038/sj.mp.4001851. K.W. Nilsson, R.L. Sjöberg, M. Damberg, J. Leppert, J. Ohrvik, P.O. Alm, et al., Role of monoamine oxidase A genotype and psychosocial factors in male adolescent criminal activity, Biol. Psychiatry 59 (2006) 121–127. http://dx.doi.org/10.1016/j. biopsych.2005.06.024. G. Frazzetto, G. Di Lorenzo, V. Carola, L. Proietti, E. Sokolowska, A. Siracusano, et al., Early trauma and increased risk for physical aggression during adulthood: the

[296]

[297]

[298]

[299]

[300]

[301]

[302]

[303] [304] [305]

[306]

[307]

[308]

[309]

135

moderating role of MAOA genotype, PLoS One 2 (2007) e486. http://dx.doi.org/ 10.1371/journal.pone.0000486. A. Reif, M. Rösler, C.M. Freitag, M. Schneider, A. Eujen, C. Kissling, et al., Nature and nurture predispose to violent behavior: serotonergic genes and adverse childhood environment, Neuropsychopharmacology 32 (2007) 2375–2383. http://dx.doi.org/ 10.1038/sj.npp.1301359. E. Levy, Localization of human monoamine oxidase-A gene to Xp11.23-11.4 by in situ hybridization: implications for Norrie disease, Genomics 5 (1989) 368–370. http://dx.doi.org/10.1016/0888-7543(89)90072-4. L. Carrel, H.F. Willard, X-inactivation profile reveals extensive variability in Xlinked gene expression in females, Nature 434 (2005) 400–404. http://dx.doi. org/10.1038/nature03479. W. Retz, P. Retz-Junginger, T. Supprian, J. Thome, M. Rösler, Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology, Behav. Sci. Law 22 (2004) 415–425. http://dx.doi.org/10.1002/bsl.589. G. Gerra, L. Garofano, G. Santoro, S. Bosari, C. Pellegrini, A. Zaimovic, et al., Association between low-activity serotonin transporter genotype and heroin dependence: behavioral and personality correlates, Am. J. Med. Genet. B Neuropsychiatr. Genet. 126B (2004) 37–42. http://dx.doi.org/10.1002/ajmg.b.20111. L. Pezawas, A. Meyer-Lindenberg, E.M. Drabant, B.A. Verchinski, K.E. Munoz, B.S. Kolachana, et al., 5-HTTLPR polymorphism impacts human cingulate–amygdala interactions: a genetic susceptibility mechanism for depression, Nat. Neurosci. 8 (2005) 828–834. http://dx.doi.org/10.1038/nn1463. A.R. Hariri, V.S. Mattay, A. Tessitore, B. Kolachana, F. Fera, D. Goldman, et al., Serotonin transporter genetic variation and the response of the human amygdala, Science 297 (2002) 400–403. http://dx.doi.org/10.1126/science.1071829 (80-.). I.W. Craig, K.E. Halton, Genetics of human aggressive behaviour, Hum. Genet. 126 (2009) 101–113. http://dx.doi.org/10.1007/s00439-009-0695-9. R.J. Knell, Population density and the evolution of male aggression, J. Zool. 278 (2009) 83–90. http://dx.doi.org/10.1111/j.1469-7998.2009.00566.x. K.A. Dodge, J.E. Lansford, V.S. Burks, J.E. Bates, G.S. Pettit, R. Fontaine, et al., Peer rejection and social information-processing factors in the development of aggressive behavior problems in children, Child Dev. 74 (2003) 374–393. http://dx.doi.org/10. 1111/1467-8624.7402004. A. Caspi, T.E. Moffitt, Gene–environment interactions in psychiatry: joining forces with neuroscience, Nat. Rev. Neurosci. 7 (2006) 583–590. http://dx.doi.org/10. 1038/nrn1925. M.A. de Souza Silva, C. Mattern, B. Topic, T.E. Buddenberg, J.P. Huston, Dopaminergic and serotonergic activity in neostriatum and nucleus accumbens enhanced by intranasal administration of testosterone, Eur. Neuropsychopharmacol. 19 (2009) 53–63. http://dx.doi.org/10.1016/j.euroneuro.2008.08.003. M.A. de Souza Silva, B. Topic, J.P. Huston, C. Mattern, Intranasal administration of progesterone increases dopaminergic activity in amygdala and neostriatum of male rats, Neuroscience 157 (2008) 196–203. http://dx.doi.org/10.1016/j.neuroscience.2008.09. 003. M.R. Laconi, P.C. Reggiani, A. Penissi, R. Yunes, R.J. Cabrera, Allopregnanolone modulates striatal dopaminergic activity of rats under different gonadal hormones conditions, Neurol. Res. 29 (2007) 622–627. http://dx.doi.org/10. 1179/016164107X166281.

Stress and the social brain: behavioural effects and neurobiological mechanisms.

Implantation and Establishment of Pregnancy in Human and Nonhuman Primates.

Transmission of human leukaemia to nonhuman primates.

The mirror system in human and nonhuman primates.

Behavioural and cognitive-behavioural interventions for outwardly-directed aggressive behaviour in people with intellectual disabilities.

Differences in auditory timing between human and nonhuman primates.

Brain mechanisms of acoustic communication in humans and nonhuman primates: an evolutionary perspective.

Freeze for action: neurobiological mechanisms in animal and human freezing.

Assessing anxiety in nonhuman primates.

Operant nociception in nonhuman primates.

Antibody-Mediated Rejection in Sensitized Nonhuman Primates: Modeling Human Biology.

Hormonal steroids and sexual communication in primates.

Distinct Lineages of Bufavirus in Wild Shrews and Nonhuman Primates.

Models of stress in nonhuman primates and their relevance for human psychopathology and endocrine dysfunction.

Small intestinal transplantation in nonhuman primates.

Amyloid precursor protein in aged nonhuman primates.

Chronic wasting disease agents in nonhuman primates.

Letter: Protein-calorie deficiency in nonhuman primates.

Secondary expansion of the transient subplate zone in the developing cerebrum of human and nonhuman primates.

Social inequalities in health in nonhuman primates.

Harms and deprivation of benefits for nonhuman primates in research.

Expression and function of beta 2 integrins on alveolar macrophages from human and nonhuman primates.

Neurobiological mechanisms of acupuncture.

SFTS virus infection in nonhuman primates.