Pharmac. Ther. Vol. 47, pp. 167-180, 1990 Printed in Great Britain. All rights reserved

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PRIMATE SOCIAL BEHAVIOR--ANXIETY OR DEPRESSION? SANDRA V. VELLUCCI Department of Anatomy, University of Cambridge, Cambridge CB2 3D Y, U.K. Almtract--A review of primate social behavior in different species is presented, with particular emphasis on the talapoin monkey and the concept of dominance and how this may be related to physiological function. Social behavior in nonhuman primates can be used to study both anxiety and depression, depending on the precise social setting employed and the way in which the animals are manipulated, for example by drugs. Studies relevant to anxiety and depression are described, and indicate that the behavior of dominant animals is more susceptible to drugs that are known to manipulate levels of anxiety, whereas subordinate animals appear more susceptible to treatment with antidepressant drugs.

CONTENTS 1. Primate Social Behavior 1.1. Background 1.2. The concept of dominance 1.3. How may dominance behavior be related to internal/physiological function? 1.4. Studies in different species of nonhuman primates 1.4.1. Talapoin monkeys 1.4.2. Squirrel monkeys 1.4.3. Vervet monkeys 1.4.4. Macaques 1.5. Stress-induced reproductive suppression 2. Drug Studies in Nonhuman Primates 2.1. Introduction 2.2. Anxiolytic and anxiogenic drugs 2.3. Depression 2.4. Antidepressant drugs 2.5. Drugs producing depression 3. Summary Acknowledgements References

1. P R I M A T E SOCIAL B E H A V I O R 1.1. BACKGROUND Numerous studies on the biology of anxiety and depression have been carried out using singly-tested animals, predominantly rodents. Such paradigms have provided a great deal of useful information concerning the neurocbemical aspects of these conditions and have been useful in predicting whether or not a given drug may be clinically effective in their treatment. However, single-animal models have limitations if one wishes to gain insight into the more subtle aspects of normal and abnormal human physiology and behavior and the way in which they may be affected by drugs. Indeed, psychiatric disorders such as anxiety and depression are, at least in part, disorders of social behavior expressed in social settings. This problem may possibly be overcome by

167 167 168 169 169 169 170 170 170 171 171 171 172 176 177 177 178 178 178

utilizing various techniques which enable the study and quantitation of the behavior of n o n h u m a n primates living in social groups similar to those that are normally characteristic of the particular species in the wild. Studies of social behavior in n o n h u m a n primates, in which the findings have been interpreted as being directly homologous with those in man, have left many questions unanswered. If one were to consider the findings within a broad context (for example, behaviors with similar functions) then a direct analogy between m a n and n o n h u m a n primates could be drawn. As will become evident, such models have proved to be extremely useful because they provide information which cannot be obtained by studying animals in nonsocial situations. There are several reasons why n o n h u m a n primates are the best available animal subjects for this type of research. Phylogenetically monkeys, apes and human beings have 167

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evolved from a common ancestor for at least 30 million years after they had separated from the other mammals. Morphologically and functionally nonhuman primates possess a very elaborate central nervous system which is, in many ways, similar to that of man. Many species of nonhuman primates live in structurally organized social groups, exhibiting a range of behaviors involving dynamic interactions with other group members, which may be directly comparable with those of humans (Sassenrath and Chapman, 1976; Raleigh and McGuire, 1980). Although the hierarchies and attachment-bonds that are formed remain relatively constant, they can be manipulated by various means, for example by altering group structure (by removing or adding members), by manipulating animal behavior pharmacologically (by treatment with hormones or psychoactive drugs), by the removal of endocrine organs, by the placement of lesions in specific regions of the central nervous system, or by changing the environmental conditions of the animals. As in the case of humans, the interactions between the social position of a nonhuman primate and its response to a drug treatment may be complex and may influence the efficacy of a given treatment (see later). Such drug effects cannot be studied satisfactorily in animals that are not socially living. This type of model is thus potentially useful for human research and, indeed, has had a long association with clinical research (McKinney and Bunney, 1969). Various types of nonhuman primate models have been developed involving observations of the behavioral interactions occurring within social groups or the behavior occurring following mother-infant or peer-peer separation, and the effects of drugs thereon, which are considered to be of relevance to human anxiety and depression. However, before relevant data obtained using these models are described, some mention will be made concerning the social behavior and social structure of some of the nonhuman primate species that have been studied, along with some of the problems that may occur in the interpretation of data obtained from such studies. Unlike many mammals that exhibit social behavior only at certain times of the year, primates live permanently in social groups. This can generate stress between group members, for example as far as access to food, mates and preferred position are concerned, but can also prove to be a useful means whereby external stressors (e.g. predators) are dealt with satisfactorily. The most important property of a social group is that it has a well-defined structure, that is, the relationships that exist between the different members of a given group are not merely random or equal (Hinde, 1974). The relationships thus formed can be divided into various classes, each of which have specific behavioral features (e.g. mother-infant relationships, interjuvenile interactions or sexual consortships). Between-class interactions can occur, e.g. an adult male is likely to respond differently to a juvenile animal than to another adult male. The second type of interaction is between the members of each class, e.g. the adult males of social groups have an overall distinct pattern of behavior but between individuals there is another set of relationships which are often

based on aggressive interactions. This determines not only their response to each other but also their access to favored objects and how they will react to a common stressor from either within or outside the group. The latter will also determine the responses they make to each other, as well as who has priority of access to favored objects (e.g. choicest food, sleeping places and receptive females). Even from early infancy, when a young monkey can understand and is concerned with only a very small part of its social group, any event that affects the group as a whole will also affect the infant, either directly, or indirectly via an effect on its mother or peers. These early social experiences, especially peer interactions, are essential for the normal emotional and behavioral development of the animal and will greatly influence the way in which an animal relates to the other members of its social group when it becomes an adult. For example Harlow and Harlow (1969) have shown that monkeys raised with peers but in the absence of a mother, grow up to be normal adults, whereas monkeys raised with only a mother show little play and no sexual behavior when adult. On the other hand, infants deprived of both maternal and peer-peer interactions become behaviorally abnormal, with mating behavior being absent and social interaction being greatly reduced in the presence of normal monkeys. Biochemical and neuroendocrine function is also altered in these animals. 1.2. THE CONCEPTOF DOMINANCE As most socially living primates form dominance hierarchies some discussion of this concept is considered relevant at this point. Problems that this may impose upon the interpretation of data in a given species and the comparison of data between species will be discussed. In addition, it is important to remember that the way in which a group member may respond to treatment with psychoactive drugs will be influenced by the rank or position held by that animal within its social group. Much social stress in animals and humans is derived from, or is expressed through, aggressive interactions. Aggression p e r se is not a unitary behavior but nearly always occurs in association with other behavioral processes. Socially living nonhuman primates form dominance hierarchies which may be defined in terms of the outcome of aggressive interactions. Thus if animal A attacks animal B, and B fails to either retaliate or initiate aggression towards A, then A is said to be dominant to B. If animal B attacks C and C attacks D, a linear hierarchy is said to exist in which A is the dominant animal. It does not necessarily follow from this that animal A is the most aggressive within the group, that is, dominance is defined on the basis of the direction of the aggression and not necessarily on the total amount of aggression given. In well-established social groups of monkeys instances of overt aggression may be rare and the dominant male is often able to deal with any conflict, or potential conflict, that has arisen by a change in facial expression or posture. Although it is possible to establish the relative position or rank of a monkey within a social group by observing the behavioral interactions that occur within that group,

Primate social behavior it is not possible by studying a monkey in complete isolation to ascribe to it the rank that it will achieve when it is placed in a new group. 1.3. H o w MAY DOMINANCE BEHAVIOR BE RELATED TO INTERNAL/PHYSIOLOGICAL FUNCTION 9•

As well as there being clearly defined differences in the types of behavior exhibited by socially living nonhuman primates according to the rank that they hold, there is also a difference in the endocrine status of the various group members. Thus a number of studies have shown that dominance status can influence circulating levels of adrenal and gonadal hormones in several primate species (Candland and Leshner, 1974; Rose et al., 1974; Coe et al., 1979; Dixson, 1980), although some authors have failed to support these findings (Eaton and Resko, 1974). Some of the differences between these studies may be explained as being due to factors that are known to influence dominance rank. For example, in the case of gonadal hormones in the male, dominance may have a more marked association with hormonal output during the mating season, and the failure of Eaton and Resko (1974) to obtain a correlation between testosterone concentrations and rank in Japanese macaques may have been due to the fact that these animals were not studied during the mating season. The effect of rank on hormone levels is more marked in competitive situations (e.g. competition for food, space or attractive females) and following agonistic encounters such as are seen during newgroup formation (Bernstein et al., 1979b). In the talapoin monkey, Keverne (1979) demonstrated that on moving into a new social group, those monkeys that became dominant showed an initial increase in cortisol and testosterone but not in prolactin, whereas those that became subordinate showed increases in cortisol and prolactin but no increase in testosterone levels. Once the social group became established, there was little further change in testosterone levels, but cortisol was found to increase still further in the subordinates, and to decrease in the dominants. This increased stress response appears to develop despite the fact that overt aggression is, at this stage, low or nonexistent. Hence the association between (plasma) hormone levels and behavior may be less obvious in well-established and stable social groups (Green et al., 1972; Bernstein et al., 1979a; Gordon et al., 1979). Some of the discrepancies which have also been noted as far as the influence of rank on hypothalamo-pituitary-adrenocortical function is concerned can also be resolved, at least in part. Various authors have reported the existence of increased adrenal cortical activity in subordinate animals (Sassenrath, 1970; Chamove and Bowman, 1978) which agrees well with observations made in rodents, whereas other studies have reported that dominant animals can have increased glucocorticoid activity (Candland and Leshner, 1974; Coe et al., 1979). On examining the information obtained it is clear that one must take into account the precise social situation under which the animals were investigated. One must distinguish, for example, social stress and overcrowding, to which subordinate animals are very susceptible, from conditions in which dominant

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animals may be more greatly affected such as exposure to a novel environment, the introduction of a strange male, or the introduction of attractive females. Thus when studying the effects of sociallyinduced stress it can be seen that the susceptibility of the different ranks will vary depending on the precise conditions under which the animals are studied. This is important when data from different, or even the same sources are being compared and also, as we shall see later, when investigating the effects of psychoactive drugs on primate social behavior. Studies that may be of possible relevance to human anxiety and depression have been carried out in various species of socially-housed nonhuman primates (e.g. talapoin and rhesus monkeys) and some of these, along with any relevant details relating to the group structure and the neurochemical and neuroendocrine profiles of the different ranks will now be reviewed. 1.4. STUDIES IN DIFFERENT SPECIES OF NONHUMAN PRIMATES

1.4.1. Talapoin Monkeys I shall start with the talapoin monkey as this is the species that we have used in our studies of the effects of anxiolytic and anxiogenic drugs on social behavior and neuroendocrine function (Vellucci et al., 1986). As mentioned earlier, established social groups of talapoin monkeys (the smallest species of Old World monkey) show a well-defined linear dominance hierarchy amongst both males and females. Thus there are rank-related differences in aggressive, sexual and social behaviors, in visual monitoring (Dixson and Herbert, 1977; Everitt et al., 1981) and cage, position, as well as in endocrine and CNS monoamine profiles (Keverne, 1979), with animals of high rank receiving little or no aggression and exhibiting more sexual and social (affiliative) behavior and less visual monitoring than the corresponding subordinate animals. On the other hand individuals of low rank receive aggression from higher ranking animals and show little or no social and sexual behavior but high levels of visual monitoring. The dominant male is not necessarily the most aggressive animal within the group, however, as stated previously, dominant males receive the least aggression, whereas subordinates receive the most. It has been shown that dominant talapoin monkeys are able to keep subordinate animals under control by the use of intermediate-ranking animals. This strategy frees the dominant male from continuous monitoring of all males in the group and aggression can be exerted towards the subordinates through the hierarchical chain of command. Such intimidation of subordinates puts them under considerable stress and it is not surprising that once the social hierarchy within a heterosexual social group has become firmly established the levels of 'stress' hormones will decrease in dominants and increase in subordinates. The concentrations of cortisol and the 5-HT metabolite 5-hydroxy-indoleacetic acid (5-HIAA) in plasma and cerebrospinai fluid (CSF) are higher in subordinate male talapoins, whereas plasma testosterone concentrations are lower in these than in other mature males housed in heterosexual social groups (Eberhart et al.,

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s. v.

1985; Yodyingyuad et al., 1985). An increase in the concentration of 5-HIAA in the CSF in usually indicative of increased release of 5-HT such as is seen in conditions of chronic stress (Curzon and Green, 1969; Kennett and Joseph, 1981; Joseph and Kennett, 1983) or in anxiety (Stein et al., 1973; File and Vellucci, 1978). In the case of females aggressive behavior is rare and the strategy that dominant females adopt is quite different. Solicits from the highest ranking females towards males are not only more frequent than from lower-ranking females, but are more likely to lead to mounting. Studies have shown that when a female solicits a male of low rank, this male receives increased aggression from the other males of the group. However, the most likely behavior to follow solicits by low-ranking females are solicits by high-ranking females. Thus the strategies that have been adopted to restrict sexual activity in low ranking nonhuman primate species, such as the talapoin, differ markedly between the sexes. Males are more likely to intimidate subordinates by the threat of impending aggression, preferably via an intermediate animal, whereas females are more likely to prevent subordinate females from being mounted, by themselves sexually soliciting the male’s attention. Thus it may be considered that in a heterosexual social group a subordinate animal is under the persistent threat of aggression from higher ranking animals and is constrained behaviorally by their constant presence. Furthermore the subordinate animal cannot escape because of the spatial confines of the cage in which it is housed for the purpose of experimental study. Thus any neuroendocrine differences that exist between dominant and subordinate animals may be considered to reflect the degree of stress to which an animal is exposed, i.e. in an established social group a subordinate animal is exposed to chronic inescapable stress, whereas a dominant animal will only experience stress more acutely (e.g. during aggressive encounters). In any event, the dominant animal will be able to control the outcome of a potentially stressful situation, whereas a subordinate animal is unable to exert any control over the situation in which he finds himself. If infrequent socio-sexual activity in subordinate males is a reflection of the fact that such animals are under the constant threat of, or receipt of aggression, then it might be thought that removing all other males from the social group would enable the subordinate to exhibit increased sexual activity. This was tested by Eberhart et al. (1983) who found that subordinate males in this situation failed to exhibit sexual behavior. This cannot be accounted for in terms of the direct receipt of aggression, nor can the differences in behavior between high and low ranking males be due to differences in female sexual initiative since females solicited the subordinates in this situation to a greater extent than dominants. Thus it is considered that the state of subordination produces a long-term effect on behavior which is not readily reversible following removal of the dominant animal(s). A brief overview of the social structure(s) and rank-related neuroendocrine differences seen between members of other species of group-living nonhuman primates will now be presented.

VELLUCCI

1.4.2. Squirrel Monkeys The relationship between dominance hierarchy and hormone levels has been examined in this species (Vogt et al., 1981; Coe et al., 1982). Higher levels of plasma cortisol are found in high-ranking males compared with subordinates. Social manipulations such as new group formation, the introduction of new females into a group and the occurrence (especially in large groups) of frequent aggressive interactions may account for these results and may be related to the dominant monkeys being in a more vigilant and aroused state. However. if the social conditions are altered such that the subordinates are forced to continually avoid dominant animals, then plasma cortisol concentrations become higher in the subordinates i.e. comparable with the neuroendocrine differences observed between dominant and subordinate talapoin monkeys. 1.4.3. Verve? Monkeys In the wild this species of Old World monkey is often found in multi-male groups, and although the dominant male from a social group can be easily identified, the ranking of subordinates is less clear-cut and their behaviors are not consistently ordered in a linear manner across a variety of measures. Thus, unlike the adult males of other species of Old World monkeys, such as the talapoin monkey, adult male vervet monkeys appear to exhibit a binary, rather than a linear dominance hierarchy. Although there is no clear evidence for a correlation between social status and plasma cortisol concentrations in stable groups of vervet monkeys (McGuire et al., 1986) there appears to be a tendency for dominant males to have the highest cortisol levels, although the ranges for dominant and subordinate animals overlap considerably. Furthermore, some reports clearly indicate that plasma cortisol levels are highest in animals that compete for dominance status, especially in those animals that eventually became dominant (McGuire et al., 1986). However, the dominant animals that were used for this work were isolated overnight prior to blood sampling and therefore the direct relevance of these values in reflecting dominance status in a group situation is questionable. 1.4.4. Macaques There is evidence for a relationship between plasma testosterone concentration and dominance in male rhesus monkeys. Following aggressive encounters, those males that were defeated showed depressed testosterone levels, whereas increases occurred in the dominant male (Bernstein et al., 1974). Unlike other species of macaque, stumptail macaques maintain a relatively constant pattern of mating behavior during the year and do not conform to the well-defined seasonal pattern characteristic of many other macaques. They also exhibit a clearly defined dominance hierarchy that remains stable over time. The behavior of macaques has been extensively studied and well-documented and this species has also been used for psychopharmacological research (Bernstein, 1980; Bernstein and Gilloud, 1965; Boelkins, 1967;

Primate social behavior Gouzoules, 1975; Rhine, 1972, 1973; Rhine and Kronenwetter, 1972). 1.5. STRESS-INDUCEDREPRODUCTIVESUPPRESSION This is another important feature exhibited by some members of primate social groups. It has been shown in many species of socially-living nonhuman primates where the groups contain more than one male, that reproductive activity is closely related to the dominance hierarchy. Dominant males copulate more frequently and sire more young than those lower in the hierarchy. Several mechanisms are believed to contribute to the reduced breeding potential of subordinate animals. They may be attacked by dominant animals if they attempt to mate; the females may show a lack of preference for them, and the levels of plasma testosterone in the subordinate males may be significantly lower than those of the dominant animals (Eberhart et aL, 1980; Rose et al., 1975). However, even if subordinates are treated with testosterone supplements, they may still fail to exhibit sexual behavior, thus indicating that factors other than hormonal deficiency may be of importance (Dixson and Herbert, 1977; Eberhart et al., 1985). Attempts have been made to establish the nature of these factors, for example whether the animal's social rank is important or whether the amount or nature of aggressive interactions are more important. For example, it has recently been shown in talapoin monkeys that there is a negative correlation between mean plasma testosterone concentrations and aggression received from other males (Martensz et al., 1987). However, it is clear that despite the existence of some degree of steroid dependence of primate sexual behavior other factors must also be taken into account, such as the evolutionary change in the complexity of the primate brain, which provides far more flexibility in the expression and hormonal regulation of these behaviors. The structure of the social group in which the animal lives is also of fundamental importance. In man social stress, as well as chronic exposure to fear-provoking situations, can also result in low plasma testosterone levels (McGrady, 1984), whereas socially dominant men, who may not necessarily be aggressive, have higher serum testosterone levels (Ehrenkranz et al., 1974). Furthermore, in nonhuman primates, if stress is applied from outside the group then the effects on the testosterone concentrations of the group members will depend on their rank. Plasma testosterone concentrations of dominant monkeys may be elevated whereas those of subordinates are lowered (Eberhart et al., 1980; Sapolsky, 1986). The female reproductive system is also affected by social stress, for example, subordinate female talapoin monkeys ovulate less frequently than dominant ones and rank is positively correlated with fertility (see Keverne and Vellucci, 1988 for review). To some extent comparable effects are observed in human females, e.g. psychological stress, anxiety or depression, are all factors that can lead to reproductive suppression. In experimental animals including rodents, stresses such as social stress, cause increased prolactin release. Furthermore, it is known that in humans prolactin has an antifertility role, thus

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suggesting a possible mechanism whereby social stress can inhibit reproductive function, and also suggesting some degree of similarity between human and nonhuman primates with respect to the reproductive inhibitory effects imposed by social stress, which in humans we know to be accompanied by the symptoms of anxiety or depression. In practice very few studies have actually been carried out in order to ascertain whether or not there are elevated prolactin levels in humans during stress. Acute stress was found not to elevate plasma prolactin levels (Nesse et al., 1980), whereas more chronic stress evoked an increase (Herbert et al., 1986). On the basis of the suggestion that impotence in men is a consequence of raised prolactin levels, Everitt et al. (1981) investigated the effects of dopamine antagonists (i.e. substances that can cause hyperprolactinemia) on the sexual behavior of male rhesus monkeys. However, the induction of hyperprolactinemia failed to produce behavioral deficits in male rhesus monkeys that could correspond with those described clinically in men. Thus although reproductive suppression is observed in subordinate monkeys as well as in humans that are anxious or depressed, the underlying neuroendocrine mechanism(s) responsible for this have not yet been fully elucidated and there is much scope for further work.

2. D R U G STUDIES IN N O N H U M A N PRIMATES 2.1. INTRODUCTION Investigations of the behavioral responses of animals following manipulation with pharmacological agents are important because: (a) the animal's response is viewed as being potentially analogous to the human response; (b) pharmacologically-induced changes in behavior are used to make inferences concerning normal species-typical behavior. Such studies have provided insight into human behavior and the possible underlying causes of psychiatric disorders, such as anxiety and depression. The two basic approaches may be extended by emphasizing the interrelationship that exists between socially-induced variables and drug effects on behavior, and the data thus obtained can be applied to psychiatric research. As disorders such as anxiety and depression are partly disorders of social behavior expressed in social settings, it is pertinent to study the drugs that are of potential use in the treatment of these conditions on animal social behavior rather than in singly-housed animals. Conversely, it may also be useful to study the effects on social behavior (and neuroendocrine parameters) of agents that are believed to mimic the biochemical deficits seen in these disorders. The following section will deal with studies on primate social behavior and neuroendocrine function, involving the use of drugs that are used clinically in the treatment of anxiety or depression and will also include data obtained from studies that have involved the use of drugs or manipulations that have evoked changes in CNS function that may

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be considered to be analogous with those occurring during anxiety or depression. 2.2. ANXIOLYTICAND ANXIOGENICDRUGS Although several authors have attempted to study the behavioral effects produced in monkeys following pharmacological manipulation with drugs that might, for example, be expected to increase or decrease anxiety by acting at benzodiazepine binding sites, most of these studies have made use of classical animal models of anxiety such as the conflict test or have utilized chair-restrained animals (Sepinwall et al., 1978; Ninan et al., 1982; Crawley et al., 1985). The effects of such drugs on the behavior of monkeys in heterosexual social groups have not been previously studied in detail. As far as talapoin monkeys are concerned, it may be considered that, as a conse-

quence of the social constraints imposed by the chronic receipt or constant threat of aggression, subordinate talapoins are chronically stressed, unlike the corresponding dominant animals which are only exposed to stress acutely (e.g. when males and females are allowed to interact) and this is reflected in the behavioral and endocrine differences observed between the two ranks. Thus, a subordinate animal is constantly exposed to a situation over which it has no control and which may have unpredictable consequences. The chronic exposure to such an environment could ultimately lead to a situation where the subordinate animal huddles in a corner, moves very little, shows high levels of visual monitoring, does not eat and ultimately succumbs to infection and dies. Therefore it may be suggested that a subordinate male talapoin could be chronically 'anxious', compared with the corresponding dominant animal, and

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Fig. l(c) FIG. 1(a-c). Aggression received and given, and visual monitoring in untreated dominant and subordinate male talapoin monkeys and following treatment of either the dominant or subordinate with 3-CCE (375 p g/kg, i.m.) or its vehicle. Each value is the mean (+ SD) of 6-8 observations. Significantly different from vehicle treatment: *p < 0.05; **p < 0.001. that perhaps a subordinate animal would be more susceptible to the pharmacological effects of an anxiolytic compound. The behavioral pattern exhibited by a subordinate talapoin monkey may also be analogous with the learned helplessness paradigm of depression described in the rat (Seligrnan, 1975). However, although studies with anxiolytic and anxiogenic compounds have been carried out in talapoin monkeys (see below) studies with antidepressant drugs have not yet been carried out. The behavioral and neuroendocrine profiles of dominant and subordinate male talapoin monkeys have been examined following treatment with either an anxiogenic drug (fl-carboline-carboxylic acid ethyl ester, fl-CCE) or an anxiolytic drug (the short-acting benzodiazepine derivative, midazolam) (Vellucci et al., 1986). ~-CCE and related esters (such as FG7142) have been shown to exhibit anxiogenic effects in rats (Lal and Shearman, 1980; Corda et al., 1983; File and Lister, 1983; Vellucci et al., 1988), rhesus monkeys (Ninan et al., 1982; Crawley et al., 1983; Petersen and Jensen, 1984) and humans (Dorow et al., 1983). When used in humans, in doses that give rise to occupation of brain benzodiazepine receptors, F G 7142 has been shown to elicit severe attacks of anxiety, not accompanied by preconvulsive EEG changes. These symptoms were rapidly reversed by the i.v. administration of the benzodiazepine derivative, lorazepam (Dorow et al., 1983), fl-CCE can be a potent convulsant in monkeys (Skolnick et al., 1983; Vellucci et al., unpublished observation). Thus the compound was administered in much lower doses than those normally employed for comparable studies in the rat. The affinity of fl-carboline derivatives for central benzodiazepine receptors is similar in both rats and monkeys and the apparently greater sensitivity of monkeys to 3-CCE may be explained

largely on the basis of pharmacokinetic factors, as it has been demonstrated that, in the rat, fl-CCE is rapidly degraded by plasma esterases, whereas in monkeys plasma degradation proceeds very slowly (Skolnick et al., 1983). The study of Vellucci et al. (1986) involved the use of captive talapoin monkeys that had lived in well-established social groups in the laboratory for 2.5 years. Four social groups were used each consisting of 3~, males and 3 4 females. The animals were housed in large cages each of which was divided into three sections. The males normally live in two-thirds of the cage with the females partitioned off in the remaining third. At the same time each day the partitions between the two parts of the cages were removed and the males and females allowed to interact for a period of 50 min (in order to maximize the amount of interaction) and their behavior recorded using a computer-linked keyboard. In dominant male talapoins, fl-CCE altered behavior in such a way that the animals exhibited an increase in aggression, reduced levels of sexual behavior and increased levels of visual monitoring. Treatment of the corresponding subordinate males served only to increase their levels of visual monitoring and had no significant effect on other behavioral parameters. Conversely, treatment with the benzodiazepine derivative midazolam, using a dose that did not elicit sedation, produced behavioral effects that were essentially opposite to those evoked by ~-CCE. Thus, when midazolam was given to the dominant animal it produced a reduction in aggressive behavior, an increase in sexual behavior and a decrease in visual monitoring. However, when the same dose of midazolam was administered to subordinate males, no significant changes were noted in their behavior. Thus, contrary to expectation, acute treatment with

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an anxiogenic (/3-CCE) or an anxiolytic (midazolam) drug was found to affect the behavior of dominant animals but not that of subordinates (see Figs l a - c and 2a-e). Possible reasons for this observation are discussed in detail later in this section. Social status has previously been shown to be an important determinant of drug effects in monkeys, with the dominant and subordinate animals exhibiting quantitatively different responses to the same drug and in some cases the opposite effects. For example, low doses of ethanol have been shown to increase the aggressive behavior of dominant squirrel monkeys without affecting that of the subordinates (Winslow and Miczek, 1985). Status-dependent effects have also been noted with amphetamine which has been shown to have no significant effects on the low levels of aggressive behavior of subordinate squirrel monkeys but markedly reduces the aggressive behavior shown by dominant monkeys (Miczek and Gold, 1983). Furthermore, the same dose of amphetamine decreased locomotor activity in dominant animals whilst increasing it in the subordinates. Other status-dependent effects of amphetamine have also been reported (Haber et al., 1981; Schlemmer and Davis, 1981, 1983). Such status-related differences in behavior could reflect actual differences in responsiveness to the drug between animals of different rank. Alternatively it is possible that dominants and subordinates are equally sensitive to centrally-acting

drugs but that the presence of the dominant male prevents (or constrains) the subordinate from exhibiting behaviors such as aggression. This has, as yet, not been studied in detail and thus the question remains unresolved. The effects of fl-CCE have previously been studied in chair-restrained baboons by Ninan et al. (1982) and Crawley et al. (1985) who suggested that the administration of this drug to monkeys could be a reliable model of human anxiety. The behavioral effects observed by these authors, which included increased vocalization, abnormal head and body movements, increased defecation, piloerection and scratching, could be readily antagonized by doses of diazepam that were within the clinical therapeutic range. These overt behavioral effects were not noted with the much lower doses of J3-CCE used by Vellucci et al. (1986) who noted behavioral effects that would not have been evident if the monkeys had not been studied within the context of an established social group. It is possible that the anxiogenic and other behavioral effects of/~-CCE may be dose-related in a manner analogous to those of pentylenetetrazole (leptazol) which is anxiogenic at low doses in man (Rodin, 1958) and animals (Lal and Shearman, 1980), whereas at high doses it elicits more dramatic behavioral effects including convulsions. Crowley et al. (1974) studied the effects of various centrally-acting drugs, including ethanol, on social behavior in a

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Fig. 2(c,d,e) FIG.2(a-e). Aggression received and given, social and sexual behavior, and visual monitoring in dominant and subordinate male talapoin monkeys treated with midazolam (125/~g/kg, i.m.) or vehicle. Each value shows the mean (+ SD) of 6-8 observations. Significantlydifferent from vehicle treatment: **p < 0.001. colony of pigtailed macaques (M. nemestrina). Single doses of various concentrations of ethanol (from 0.5 to 2.0ml/kg) were administered via a naso-gastric tube to the 5 males that ranked immediately below the dominant male, with only one subject being treated at any given time. In the absence of any drug treatment the dominant male prevented the other males from mounting and copulating with females (thus in the absence of drug treatment 10% of the

observed sexual behavior was heterosexual in nature and 90% was autosexual). Although treatment with ethanol did not change the absolute amount of sexual behavior it dramatically altered the relative proportions of these behaviors. Thus, with the highest dose of ethanol, more than 90% of the sexual behavior shown by the treated subordinate males was heterosexual, Ethanol did not affect the relative proportions of dominant or submissive behaviors. Winslow and

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Miczek (1985) studied the effects of ethanol in established social groups of squirrel monkeys and found that it produced differential behavioral effects in dominant and subordinate males. When one considers the nature of the social structure of groups of talapoin monkeys, and the observed differences in behavior and neuroendocrine parameters between dominant and subordinate monkeys, it might be expected that, with the type of drug treatment used by Vellucci et al. (1986) the most marked effects would have been on the subordinate animals as these may be considered to be the most 'anxious' within a given social group. However, that is not to say that dominant monkeys are not anxious, and indeed during the period of interaction between males and females there are increases in aggressive encounters within the group brought about by the presence of receptive females, because the dominant animal has to maintain both his rank and the integrity of the group. This is obviously stressful but only acutely so; in any event the dominant animal is generally in command of the situation in which it finds itself, whereas a subordinate is not. These observations in talapoins are in accord with observations made by Insel et al. (1988) who investigated two groups of socially housed rhesus monkeys raised under conditions differing in the degree of control or 'mastery' over appetitive stimuli in the first year of life. The so-called 'learned mastery' animals (i.e. those having the ability to control access to food and water by means of lever pressing) were paired with 'yoked controls' who obtained identical appetitive stimuli, but only at times chosen by the 'learned mastery' group. This difference in controllability was associated with significant behavioral differences at 7-10 months of age, with the 'learned mastery' group demonstrating less fearful behavior and more exploratory behavior when challenged by environmental stressors and exposure to novelty (Mineka et al., 1986). In their own environment there was very little behavioral difference between the two groups, with the animals reared in conditions of uncontrollability (i.e. the yoked group) appearing slightly more passive and less playful. The only significant group differences were the higher plasma cortisol concentrations in the yoked group. When the animals were approximately two years of age they received/~-CCE under the assumption that the 'learned mastery' group would be more resistant to the effects of/~-CCE than the yoked group. However, although there were differences between the 2 groups, the most dramatic effects were observed in the 'learned mastery' group. This group responded with a very marked increase in aggressiveness, especially towards the observer, whereas the 'yoked controls' showed an increase in fearfulness. When the study was terminated the animals were placed in new social groups and it was subsequently noted that the 'learned mastery' animals became the dominant members of the group whereas the 'yoked controls' became the subordinates. These results suggest that early experience with controllability may have long-term consequences on social behavior and social status. This may also have relevance to humans in that individuals brought up in an environment where they always lack 'controllability' may be more prone to developing psychiatric disor-

ders, such as anxiety or depression, than others placed in a similar situation. Further studies on this aspect of primate sociobiology would be most useful in attempting to answer this question. At this point it is interesting to note that the degree of support received from others in adulthood may also help in coping with social stress thus reducing the likelihood of occurrence of psychiatric problems. The organism's response to a stressful situation depends not only on the severity and type of stress but also on past experience and available options for coping with such a stress. Thus increases in plasma glucocorticoid concentrations can be caused by psychological stress and the animal's ability to predict and control aspects of the aversive or stressful situation can facilitate coping and, in certain circumstances, reduce the physiological or behavioral manifestations of the stress (Lazarus, 1968; Gal and Lazarus, 1975; Hennessy and Levine, 1979). This aspect has been studied in nonhuman primate species such as the squirrel monkey in which it has been shown, for example, that the presence of conspecifics can reduce the neuroendocrine response to psychological stress (Stanton et al., 1985). Finally, under this heading the effects of ethanol will be considered. It is well-established that ethanol administered acutely in low doses has anxiolytic properties in rodents tested using the active social interaction test (File and Vellucci, 1978) and in nonhuman primates tested in a conflict paradigm (Glowa and Barett, 1976). Studies relating to the effects of ethanol on primate social behavior have concentrated mainly on its effects on aggression (Miczek et al., 1984; Winslow and Miczek, 1985), on the response to social separation (McKinney et al., 1983) or on the possible reasons for the development of alcohol dependence (Crowley et al., 1983; Crowley and Andrews, 1987). The observations of Winslow and Miczek (1985), who studied the behavioral effects of ethanol administered to squirrel monkeys in established social groups, are relevant here as there are similarities between their findings and the effects that have been noted with midazolam and fl-CCE in talapoin monkeys (Vellucci et al., 1986). Winslow and Miczek (1985) found that ethanol produced a biphasic, dose-dependent change in the behavior of squirrel monkeys, with high doses suppressing aggression and low doses increasing aggression in dominant animals~ whereas the subordinates were generally unaffected by any of the doses used. 2.3. DEPRESSION

A primate model which is thought to have many features that reflect aspects of human depression is the separation model, consisting of either motherinfant separation (Suomi and Harlow, 1977), or peer-peer separation (Suomi, 1970). For example, following the separation of young rhesus monkeys from their mothers or peers a severe syndrome occurs, described as 'despair', which may ultimately lead to the development of life-threatening illness and may involve failure to maintain an adequate intake of food and water, lethargy, withdrawal and nonresponsiveness to external stimuli (see McKinney et al., 1983 for review). Mother-infant relationships are obvi-

Primate social behavior ously important but these are of comparatively short duration. From an early age a young monkey will form close relationships with other group members which will persist and continue to play a vital role during the adult life of the animal and include behaviors such as play, sexual behavior and food gathering. Dominance hierarchies are developed and the infant learns to take its place within the social group. It is well-established that rhesus monkeys experiencing social isolation or long periods of separation during their first year of life subsequently exhibit disturbances in social behavior (Hinde and SpencerBooth, 1971; Suomi et al., 1971; Capitanio and Reite, 1984) and in their response to drug treatment (Kraemer et al., 1984) during adult life. The separation model is considered in more detail in the chapter by Suomi and will therefore only be considered further where direct relevance to the present chapter is shown. That maternal separation or peer-peer separation is a valid model of human depression is confirmed by the observation that treatment with clinically useful antidepressant drugs such as imipramine can produce a significant improvement in behavior with a time course similar to that observed clinically (e.g. Suomi et al., 1978). 2.4. ANTIDEPRESSANTDRUGS Clinically amphetamine is not an effective antidepressant when used chronically, although some data has suggested that it may have short-term antidepressant properties. Evidence from studies by McKinney et al. (1983) have indicated that in restricted circumstances, amphetamine reduces despair behavior in socially-separated rhesus monkeys. In this respect it is similar to imipramine and it could therefore be suggested that amphetamine has antidepressant properties. However these are limited as, unlike imipramine, amphetamine was also found to disrupt social behavior at doses that exert antidepressant effects, producing dose-related increases in agonistic behavior. Ethanol may also be considered at this point. The relationships between ethanol and depression in humans are very complex. Humans sometimes drink in an effort to treat their depression; however, any euphoric effects are temporary and quickly evolve into depressant effects. Studies carried out in rhesus monkeys have demonstrated that, whereas high doses of ethanol produced effects that were indicative of increased depression, treatment with lower doses had clear antidepressant effects (Kraemer et al., 1981). In this study ethanol was administered to juvenile rhesus monkeys (25% ethanol, in doses of 1, 2 or 3 g/ks/day). The dose levels were chosen so that they produced large, moderate or minimal acute effects on behavior. With the higher doses, social behavior was altered in the peer housing condition as well as in the separation condition, by producing a more severe despair response than that noted with placebo. The lowest dose of ethanol decreased the incidence of huddling and passive behaviors during separation, compared with placebo, thus resulting in a less severe despair response. This dose of ethanol significantly ameliorated the response to separation without affecting the deJPT 4 7 / 2 ~

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spair response in the group-housing condition. Thus alcohol has a biphasic action in the separation model, at a low dose it behaved like an antidepressant, whereas at higher doses it exerted depressant effects. 2.5. DRUGS PRODUCING DEPRESSION Drugs that interfere with the function of monoaminergic systems have been shown to produce the symptoms of depression and the following have been investigated in nonhuman primates. (a) Drugs affecting catecholamine systems. Redmond et al. (1971) treated two adult female macaques living in a social group, consisting of one adult male and two other females, with the catecholamine synthesis inhibitor g-methyl-p-tyrosine (~tMPT). Following control observations the two subjects then received 160-250 mg/kg of gMPT, an amount calculated to produce a 50-80% depletion of dopamine and noradrenaline lasting up to 16 hr. To maintain depletion the animals received additional ~MPT every 12 hr. Following drug treatment there were quantifiable changes in social interaction and appearance. Both subjects initiated fewer social interactions including grooming, threats (despite the fact that one of the animals had been comparatively dominant), and attacks (although total social responses and socio-sexual presentations remained stable). The animals also showed reduced locomotor activity and changes in posture and facial expression suggesting withdrawal and lack of concern with the environment. Although it is not necessarily appropriate to draw direct analogies between different animal species, for example--depression and sadness are best referred in the context of human behavior, the effects produced by ~tMPT in nonhuman primates described by Redmond et al. (1971) bear a striking resemblance to the behavioral description of depression in humans. Furthermore it is interesting to note that the behavioral features described following treatment of macaques with ctMPT are very similar to the behavioral patterns exhibited by subordinate male talapoin monkeys. In view of this it would be useful to investigate the effects of antidepressant drugs in subordinate male talapoins as this has not yet been done. Finally, reserpine also produces depressive states that are clinically indistinguishable from the naturally-occurring types observed in a small percentage of humans and it is used to produce an animal model of depression. When administered to monkeys reserpine produced behavioral features similar to those described by Redmond et al. (1971). (b) Drugs affecting 5 - H T systems. Raleigh and McGuire (1980) carried out extensive studies of the effects of drugs known to influence central serotoninergic function on social behavior in vervet monkeys. The drugs used were L-tryptophan and 5-HTP (which increase brain 5-HT content and turnover, respectively), p C P A (which reduces brain 5-HT by inhibiting tryptophan hydroxylase noncompetitively) and chlorgyline (a monoamine oxidase inhibitor, which will thus enhance the activity of other monoamines as well as 5HT). These authors reported that tryptophan loading led to calmer, more tranquil animals, whereas the administration o f p C P A produced irritability and

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aggression. However, the precise response seen depended upon the social rank of the animal. For example, following the administration of etryptophan (20 mg/kg/day), the males exhibited an increase in approaching, grooming, resting and eating and a decrease in locomotor activity, solitary behavior, vigilance and avoidance. The changes were found to be more rapid and of a greater magnitude in dominant males. Relative to subordinate males, the dominant males responded to the tryptophan load with a greater absolute and relative increase in whole blood serotonin concentration (Brammer et al., 1983). The 5-HT uptake inhibitor, fluoxetine, and the 5-HT receptor antagonist, quipazine, evoked statusrelated behavioral effects similar to those seen with e-tryptophan (Raleigh et al., 1985). It is believed that pharmacologically-induced changes in 5-HT systems exert permissive effects on behavior, thus it is possible that the subordinate males may be constrained from exhibiting overt changes in behavior by the continued presence of the dominant male (Fairbanks et al., 1978). As Ltryptophan, fluoxetine and quipazine act via different mechanisms, it is considered unlikely that differences in drug metabolism or transport could account for the rank-related differences in behavior. An alternative explanation is that dominant and subordinate animals differ in their CNS responses to drugs. Preliminary studies by Brammer et al. (1987) indicated that there were no differences in the properties of the 5-HT 2 binding sites of dominant and subordinate animals. However this observation does not exclude the possibility that there are differences in other 5-HT receptor sites. The data of these authors also indicates that there is a relationship between the social role of a treated animal and the behavioral changes in nontreated animals. In the case of established social groups of vervet monkeys, chronic treatment with p C P A (80 mg/kg daily for 14 days) caused irritability, increased aggression and hyperactivity. Changes in a treated animal may alter the behavior of the other group members, depending on which animal receives the drug (e.g. when the dominant is treated the degree of social disruption among the other members of the group is far greater than if a lower-ranking animal had been treated). Thus both metabolic factors and social variables (mediating their effects through various neuroendocrine/ metabolic systems contribute to these behavioral differences.

3. S U M M A R Y F r o m the data reviewed here it is evident that social behavior in n o n h u m a n primates can be used to study both anxiety and depression depending on the social setting employed and the way in which the animals are manipulated. In established social groups of monkeys the way in which an animal responds to a given situation or manipulation is closely dependent on the position or rank that the animal occupies within the group and also on the prior experience(s) of that animal during early life. A study of the neuroendocrine, neurochemical and behavioral profiles of dominant and subordinate monkeys indicates

that the behavior of dominant animals is more susceptible to drugs that are known to manipulate levels of anxiety, whereas subordinate animals appear to be more susceptible to treatment with antidepressant drugs. Acknowledgements--I wish to thank the MRC for financial

support. I am also grateful to Trevor Humby for helpful comments.

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