Pharmacology, Biochemistry and Behavior 121 (2014) 1–2
Contents lists available at ScienceDirect
Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh
Editorial
Guest editorial: Pharmacology of female sexual behavior
Female sexual behavior has been studied over the last decades from many perspectives, e.g. biological function, endocrinology and brain mechanisms, but is has never developed into a big research area. However, in the last decade an increasing interest in dysfunctional sexual behavior in women has emerged including search for potential pharmacological treatment of various sexual dysfunctions. Low sexual desire is the most common sexual complaint in women that suffer from sexual dissatisfaction and negative effects on daily quality of life. Remarkably, no drugs treating such ‘sexual dysfunctions’ are available, although some interesting developments are underway. It seems timely to report on a new research area, the pharmacology of female sexual behavior, as knowledge of mechanisms in the brain involved in all aspects of sexual functioning is remarkably meager. If we want to be successful in the discovery and development of much needed therapeutic drugs, fundamental insight in all these processes is needed. The present special issue reflects some of the translational research in the field and clearly illustrates the need for more research. The present special issue will present research findings, from rodent and human studies, not only on the pharmacological and functional aspects of normal sexual functions, but also on female sexual dysfunctions. 1. Models The special issue starts with a review by Ågmo in which he delineates basic aspects of female sexual behavior from an animal model perspective. He describes aspects of female hypoactive desire disorder, sexual arousal disorder and orgasmic disorder in the perspective of epidemiology and motivational problems. A translational model of incentive motivation of sexual behavior is outlined and he elegantly places that in the context of the model. The comparison between female rat and female human is nicely discussed along with neurobiological mechanisms putatively involved in female sexual behavior and dysfunctions. He places future development of drugs for female sexual dysfunction disorders in a critical perspective. 2. Mechanisms and pharmacology Veening and Coolen give a comprehensive description of neural mechanisms involved in female sexual behavior comparing it with male ejaculatory control mechanisms. This elegant review points to the similarities of the neural mechanisms involved in males and females, although clear gender-specific differences are present. They point to an intriguing brain area, the ventrolateral part of the Ventromedial Hypothalamic Nucleus (VMHvl) in which integration of opposite
http://dx.doi.org/10.1016/j.pbb.2014.03.007 0091-3057/© 2014 Published by Elsevier Inc.
behaviors like aggression and sexual behavior is regulated. In addition, they point to the enormous gap in our knowledge and understanding of neural mechanisms and neurotransmission involved in the very complex brain regulation of sexual behavior. This knowledge is necessary to have an optimal chance to understand not only normal functions but also deviations in these complex networks which might help us in getting better treatments. Uphouse gives a fascinating and extensive review of the serotonergic involvement in female sexual behavior. She presents evidence that modifying serotonergic activity has either inhibiting (increased 5-HT) or facilitating (decreased 5-HT) effects on female sexual activities. Effects of several dugs interacting with different 5-HT receptors indicate that activation of 5-HT1A receptors inhibits, whereas activation of 5-HT2 and 5-HT3 receptors facilitates female sexual behavior. Most research data are collected on lordosis, a consummatory sexual behavior, whereas data on other aspects of female sexual behavior (introductory behavior e.g.) are very scarce. Snoeren and colleagues focus specifically on the role of 5-HT1A receptors in sexual behavior in female rats, comparing differences and similarities with male rats. They conclude that 5-HT1A receptors are not involved in sexual behavior under normal circumstances, but only in a challenged (enhanced 5-HT activity) condition. 5-HT1A receptor agonists seem to exert contrasting effects in male and female sexual behaviors. They facilitate male sexual behavior (prosexual effects) but inhibit female sexual behavior (at least lordosis). The authors propose an interesting hypothesis that tries to eliminate the male/female contrast in their sexual response to 5-HT1A receptor agonist. This clearly needs more investigations. Guarraci and Bolton review gender differences in sensitivity to psychomotor stimulation. They focus on research on how drugs of abuse interact with natural rewards, in this case sexual behavior in females using a variety of animal models of motivated (sexual) behavior. By measuring appetitive behaviors, sexual motivation can be studied, a human equivalent of desire. Studying the effects of abused drugs (amphetamine, methamphetamine, caffeine and cocaine) in these paradigms, the authors delineate an important role for dopaminergic neurotransmission in sexual motivation. These findings advance our knowledge and understanding of (sexual) motivation and may explain how psychomotor stimulants affect males and females differently. Levin reviews the pharmacology of the human female orgasm. Because our understanding of the physiology and especially the neurophysiology is very limited, the pharmacology of female orgasm is practically lacking. Most data seem derived from side effects of drugs which blurs the picture. Levin nicely describes the physiological processes involved in the female orgasm, including the ‘orgasm in the brain’,
2
Editorial
describing the problems of trying to visualize an orgasm in a scanner. Although our knowledge about pharmacological, hormonal and neurochemical influences on female orgasm is limited, this review is very helpful in understanding the research issues that have to be resolved (including the lacking placebo research) and pleads for more research for this important field. Finally, Poels and colleagues describe the development of two novel drugs for women with hypoactive sexual desire disorder. Low sexual desire is a very common complaint in women. The DSM-5 diagnosis Female Sexual Interest/Arousal (FSIA) disorder is a merger of earlier diagnoses Hypoactive Sexual Desire Disorder (HSDD) and Female Sexual Arousal Disorder (FSAD). No drug treatment is presently available for these conditions but there certainly is a high unmet need. The research group involved very cleverly delineated a personalized sexual medicine on demand approach, based on two different mechanisms causing low sexual desire in women; one is an insensitive system for sexual cues, and the other implies dysfunctional activation of sexual inhibitory mechanisms. By combining testosterone with a PDE5 inhibitor, or
testosterone with a 5-HT1A receptor agonist, on-demand treatment for both types of dysfunctional sexual systems has been developed and proved effective in phase 2 studies. In the coming years, further clinical investigations (phase 3) have to show the value of these approaches in FSIA. An exciting new therapeutic approach and area! We hope that this special issue will provide and support a valuable framework for future research in a somewhat underdeveloped area. The prospect of future therapy for female sexual dysfunctions is exciting. Much research and investment will be needed to bring the field of female sexual behavior/dysfunctions on a highly needed level. Berend Olivier* Marcel Waldinger Utrecht University, The Netherlands *Corresponding author at: Dept. of Psychopharmacology, Utrecht University, Universiteitsweg 99, 3584CG Utrecht, The Netherlands E-mail address: [email protected] (B. Olivier).
Contents lists available at ScienceDirect
Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh
Editorial
Guest editorial: Pharmacology of female sexual behavior
Female sexual behavior has been studied over the last decades from many perspectives, e.g. biological function, endocrinology and brain mechanisms, but is has never developed into a big research area. However, in the last decade an increasing interest in dysfunctional sexual behavior in women has emerged including search for potential pharmacological treatment of various sexual dysfunctions. Low sexual desire is the most common sexual complaint in women that suffer from sexual dissatisfaction and negative effects on daily quality of life. Remarkably, no drugs treating such ‘sexual dysfunctions’ are available, although some interesting developments are underway. It seems timely to report on a new research area, the pharmacology of female sexual behavior, as knowledge of mechanisms in the brain involved in all aspects of sexual functioning is remarkably meager. If we want to be successful in the discovery and development of much needed therapeutic drugs, fundamental insight in all these processes is needed. The present special issue reflects some of the translational research in the field and clearly illustrates the need for more research. The present special issue will present research findings, from rodent and human studies, not only on the pharmacological and functional aspects of normal sexual functions, but also on female sexual dysfunctions. 1. Models The special issue starts with a review by Ågmo in which he delineates basic aspects of female sexual behavior from an animal model perspective. He describes aspects of female hypoactive desire disorder, sexual arousal disorder and orgasmic disorder in the perspective of epidemiology and motivational problems. A translational model of incentive motivation of sexual behavior is outlined and he elegantly places that in the context of the model. The comparison between female rat and female human is nicely discussed along with neurobiological mechanisms putatively involved in female sexual behavior and dysfunctions. He places future development of drugs for female sexual dysfunction disorders in a critical perspective. 2. Mechanisms and pharmacology Veening and Coolen give a comprehensive description of neural mechanisms involved in female sexual behavior comparing it with male ejaculatory control mechanisms. This elegant review points to the similarities of the neural mechanisms involved in males and females, although clear gender-specific differences are present. They point to an intriguing brain area, the ventrolateral part of the Ventromedial Hypothalamic Nucleus (VMHvl) in which integration of opposite
http://dx.doi.org/10.1016/j.pbb.2014.03.007 0091-3057/© 2014 Published by Elsevier Inc.
behaviors like aggression and sexual behavior is regulated. In addition, they point to the enormous gap in our knowledge and understanding of neural mechanisms and neurotransmission involved in the very complex brain regulation of sexual behavior. This knowledge is necessary to have an optimal chance to understand not only normal functions but also deviations in these complex networks which might help us in getting better treatments. Uphouse gives a fascinating and extensive review of the serotonergic involvement in female sexual behavior. She presents evidence that modifying serotonergic activity has either inhibiting (increased 5-HT) or facilitating (decreased 5-HT) effects on female sexual activities. Effects of several dugs interacting with different 5-HT receptors indicate that activation of 5-HT1A receptors inhibits, whereas activation of 5-HT2 and 5-HT3 receptors facilitates female sexual behavior. Most research data are collected on lordosis, a consummatory sexual behavior, whereas data on other aspects of female sexual behavior (introductory behavior e.g.) are very scarce. Snoeren and colleagues focus specifically on the role of 5-HT1A receptors in sexual behavior in female rats, comparing differences and similarities with male rats. They conclude that 5-HT1A receptors are not involved in sexual behavior under normal circumstances, but only in a challenged (enhanced 5-HT activity) condition. 5-HT1A receptor agonists seem to exert contrasting effects in male and female sexual behaviors. They facilitate male sexual behavior (prosexual effects) but inhibit female sexual behavior (at least lordosis). The authors propose an interesting hypothesis that tries to eliminate the male/female contrast in their sexual response to 5-HT1A receptor agonist. This clearly needs more investigations. Guarraci and Bolton review gender differences in sensitivity to psychomotor stimulation. They focus on research on how drugs of abuse interact with natural rewards, in this case sexual behavior in females using a variety of animal models of motivated (sexual) behavior. By measuring appetitive behaviors, sexual motivation can be studied, a human equivalent of desire. Studying the effects of abused drugs (amphetamine, methamphetamine, caffeine and cocaine) in these paradigms, the authors delineate an important role for dopaminergic neurotransmission in sexual motivation. These findings advance our knowledge and understanding of (sexual) motivation and may explain how psychomotor stimulants affect males and females differently. Levin reviews the pharmacology of the human female orgasm. Because our understanding of the physiology and especially the neurophysiology is very limited, the pharmacology of female orgasm is practically lacking. Most data seem derived from side effects of drugs which blurs the picture. Levin nicely describes the physiological processes involved in the female orgasm, including the ‘orgasm in the brain’,
2
Editorial
describing the problems of trying to visualize an orgasm in a scanner. Although our knowledge about pharmacological, hormonal and neurochemical influences on female orgasm is limited, this review is very helpful in understanding the research issues that have to be resolved (including the lacking placebo research) and pleads for more research for this important field. Finally, Poels and colleagues describe the development of two novel drugs for women with hypoactive sexual desire disorder. Low sexual desire is a very common complaint in women. The DSM-5 diagnosis Female Sexual Interest/Arousal (FSIA) disorder is a merger of earlier diagnoses Hypoactive Sexual Desire Disorder (HSDD) and Female Sexual Arousal Disorder (FSAD). No drug treatment is presently available for these conditions but there certainly is a high unmet need. The research group involved very cleverly delineated a personalized sexual medicine on demand approach, based on two different mechanisms causing low sexual desire in women; one is an insensitive system for sexual cues, and the other implies dysfunctional activation of sexual inhibitory mechanisms. By combining testosterone with a PDE5 inhibitor, or
testosterone with a 5-HT1A receptor agonist, on-demand treatment for both types of dysfunctional sexual systems has been developed and proved effective in phase 2 studies. In the coming years, further clinical investigations (phase 3) have to show the value of these approaches in FSIA. An exciting new therapeutic approach and area! We hope that this special issue will provide and support a valuable framework for future research in a somewhat underdeveloped area. The prospect of future therapy for female sexual dysfunctions is exciting. Much research and investment will be needed to bring the field of female sexual behavior/dysfunctions on a highly needed level. Berend Olivier* Marcel Waldinger Utrecht University, The Netherlands *Corresponding author at: Dept. of Psychopharmacology, Utrecht University, Universiteitsweg 99, 3584CG Utrecht, The Netherlands E-mail address: [email protected] (B. Olivier).
