Protein Appetite Drives Macronutrient-Related Differences in Ventral Tegmental Area Neural Activity.

Control of protein intake is essential for numerous biological processes as several amino acids cannot be synthesized de novo, however, its neurobiological substrates are still poorly understood. In the present study, we combined in vivo fiber photometry with nutrient-conditioned flavor in a rat model of protein appetite to record neuronal activity in the VTA, a central brain region for the control of food-related processes. In adult male rats, protein restriction increased preference for casein (protein) over maltodextrin (carbohydrate). Moreover, protein consumption was associated with a greater VTA response, relative to carbohydrate. After initial nutrient preference, a switch from a normal balanced diet to protein restriction induced rapid development of protein preference but required extensive exposure to macronutrient solutions to induce elevated VTA responses to casein. Furthermore, prior protein restriction induced long-lasting food preference and VTA responses. This study reveals that VTA circuits are involved in protein appetite in times of need, a crucial process for animals to acquire an adequate amount of protein in their diet.SIGNIFICANCE STATEMENT Acquiring insufficient protein in one's diet has severe consequences for health and ultimately will lead to death. In addition, a low level of dietary protein has been proposed as a driver of obesity as it can leverage up intake of fat and carbohydrate. However, much remains unknown about the role of the brain in ensuring adequate intake of protein. Here, we show that in a state of protein restriction a key node in brain reward circuitry, the VTA, is activated more strongly during consumption of protein than carbohydrate. Moreover, although rats' behavior changed to reflect new protein status, patterns of neural activity were more persistent and only loosely linked to protein status.

CaMKIIa+ neurons in the bed nucleus of the stria terminalis modulate pace of natural reward seeking depending on internal state.

This study aims to investigate the underlying neurobiological mechanisms that regulate natural reward seeking behaviors, specifically in the context of sexual behavior and sucrose self-administration. The role of CaMKIIa+ neurons in the bed nucleus of the stria terminalis (BNST) was explored using chemogenetic silencing and -stimulation. Additionally, the study examined how these effects interacted with the internal state of the animals. Through detailed behavioral analysis, it was demonstrated that CaMKIIa+ neurons in the BNST play a significant role in the regulation of both sexual behavior and sucrose self-administration. Although the behavioral outcome measures differed between the two behaviors, the regulatory role of the CaMKIIa+ neurons in the BNST was found to converge on the modulation of the pacing of engagement in these behaviors in male rats. Moreover, our study confirmed that the internal physiological state of the animal affects how the BNST modulates these behaviors. These findings suggest that different types of natural rewards may recruit a similar brain circuitry to regulate the display of motivated behaviors. Overall, this research provides valuable insights into the neural mechanisms underlying natural reward seeking and sheds light on the interconnected nature of reward-related behaviors in male rats.

Chronic paroxetine treatment does not affect sexual behavior in hormonally sub-primed female rats despite 5-HT1(A) receptor desensitization.

INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) cause sexual dysfunctions in humans. However, because SSRIs are used to treat depression, it is unclear whether the problems are caused by the drug, by the depression itself, or an interaction between both. AIM: The present study investigated the effects of chronic paroxetine treatment on sexual behavior in female rats. Furthermore, we tested whether 5-hydroxytryptamine (5-HT)1(A) receptors were desensitized in these females. METHODS: Ovariectomized female rats, either sub-primed with estradiol or fully primed with estradiol and progesterone, were tested in a paced mating test. Proceptive (darting and hopping), receptive (lordosis), and paced mating-related (percentages of exits and contact-return latencies) behaviors were quantified during the course of 56 days of chronic paroxetine treatment (10 mg/kg and 20 mg/kg per day). The 5-HT1(A) /5-HT7 receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide ((±)8-OH-DPAT) alone and in combination with the selective 5-HT1(A) receptor antagonist WAY-100635 was administered to study putative 5-HT1(A) desensitization in the same females. MAIN OUTCOME MEASURES: Proceptive, receptive, and paced mating behaviors were quantified. RESULTS: Acute and chronic paroxetine treatment did not change proceptive and receptive behaviors in both sub-primed and fully primed female rats. In all groups, (±)8-OH-DPAT showed a clear dose-dependent inhibition of sexual behaviors in vehicle-treated females and a right-shifted dose-response effect in the paroxetine-treated rats. WAY-100635 attenuated the inhibiting effect of the 5-HT1(A) receptor agonist in all females. These data suggest 5-HT1(A) receptor desensitization after chronic paroxetine treatment. CONCLUSIONS: Chronic paroxetine treatment does not cause sexual side effects in sub- or fully hormonally primed female rats. Furthermore, chronic treatment causes adaptive changes in the serotonin system such as desensitization of 5-HT1(A) receptors, which may counteract the inhibiting effects of increased extracellular serotonin levels in the chronic paroxetine-treated rats.

The serotonin transporter plays an important role in male sexual behavior: a study in serotonin transporter knockout rats.

INTRODUCTION: Serotonin (5-HT) is an important neurotransmitter for sexual behaviors. Heterozygous (+/-) serotonin transporter (SERT) rats and SERT knockout rats (-/-) have serotonergic disturbances with significant elevations of basal extracellular 5-HT levels. AIM: To investigate the putative role of the SERT in male sexual behavior. METHODS: After extensive sexual training, the effects of the 5-HT(1A/7) receptor agonist ± 8-OH-DPAT, the 5-HT(1A) receptor antagonist WAY100 635 and a combination of both on sexual behaviors of SERT(-/-) and SERT(+/-) knockout and wildtype (SERT(+/+) ) male Wistar rats were examined. MAIN OUTCOME MEASURES: Male rat sexual behaviors of mounts, intromissions, and ejaculations. RESULTS: SERT(-/-) had lower basal ejaculation frequencies than SERT(+/-) and SERT(+/+) animals. ± 8-OH-DPAT enhanced sexual performance in all three genotypes to the same extent. WAY100635 dose-dependently inhibited sexual behavior in all three genotypes with significant dose to genotype interactions. WAY100635 exerted the strongest effects in SERT(-/-) animals. The combination of a dose range of ± 8-OH-DPAT and a selected dose of WAY100635 revealed only partial antagonism by ± 8-OH-DPAT of the sexual inhibitory effects of WAY100635. CONCLUSIONS: Absence of the serotonin transporter reduces basal ejaculatory performance in male rats. Pharmacological experiments suggest that separate pools of 5-HT(1A) receptors regulate different aspects of sexual performance in male rats. 5-HT(7) receptors may play a minor role in the partial recovery of sexual behavior after combination of ± 8-OH-DPAT and WAY100635. The SERT(-/-) rat may be a model for chronic SSRI treatment, delayed ejaculation, anorgasmia, and/or low libido.

A new female rat animal model for hypoactive sexual desire disorder; behavioral and pharmacological evidence.

INTRODUCTION: Female sexual dysfunction (FSD) affects 33-48% of women. Female rats with low sexual activity might model FSD. AIM: In this study, we have investigated whether in a population of normal female rats, subpopulations of rats exist with different levels of sexual behavior. METHODS: Sexually experienced, intact, estradiol-primed female rats were placed in an empty compartment adjacent to a compartment with a male. The females were allowed, during 30 minutes, to switch between the compartments via a hole through which only the females could pass (paced mating). Next, we investigated the acute effects on female sexual behavior of apomorphine, a D(1) - and D(2) -type dopamine receptor agonist, (+/-)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (± 8-OH-DPAT), a 5-HT1A receptor agonist, and paroxetine, a selective serotonin reuptake inhibitor. MAIN OUTCOME MEASURES: Time spent in compartments, proceptive behaviors, contact-return latencies, and percentages of exits were quantified. RESULTS: Based on their behavior in the paced mating sex test, estradiol-primed, intact female rats can be divided into three groups: those that mostly avoid the male, a large middle group, and those that mostly approach the male. The avoiders also showed significantly less proceptive behavior than the male approachers. The sexual behavior of the females was relatively stable over time, suggesting the existence of different endophenotypes in female rats. Apomorphine and ± 8-OH-DPAT had an inhibiting effect on sexual behavior, but only females dosed with apomorphine showed a different response in avoiders and approachers, more inhibiting effect in avoiders than approachers. Paroxetine had no effect on proceptive behavior. DISCUSSION: The stable, male-avoiding behavior of some females might correspond to the characteristics of women with FSD. Therefore, these avoiders are a promising new model for FSD, specifically for sexual desire and/or arousal disorders. Furthermore, the apomorphine data suggest that differences in the dopamine system may (partly) underlie the differences in sexual behaviors between avoiders and approachers.

Combination of testosterone and vardenafil increases female sexual functioning in sub-primed rats.

INTRODUCTION: Hypoactive sexual desire disorder (HSDD) is a common problem in women and may have a negative impact on quality of life. A recent clinical study shows an increase in sexual drive of HSDD women after cotreatment of testosterone and vardenafil (phosphodiesterase type 5 inhibitor). AIM: In this study, we investigated the effect of testosterone and vardenafil on sexual activity in female rats. MAIN OUTCOME MEASURES: Proceptive (darts and hops), receptive (lordosis), and paced-mating (percentages after exits and contact-return latencies) behaviors were quantified. METHODS: Ovariectomized female rats, sub-primed with only estradiol and fully primed with estradiol and progesterone, were tested in a paced-mating sex test and sexual behaviors were quantified. The sub-primed rats are thought to model HSDD. The effect of testosterone (100 and 300 µg, subcutaneous [SC]) and vardenafil (10 mg/kg, per os [PO]) alone and testosterone (300 µg, SC) in combination with vardenafil (3 and 10 mg/kg, PO) were tested. We also studied the effects of testosterone (300 µg, SC) + intracerebroventricular (ICV) injections of vardenafil (25 and 50 µg) on sexual activity. RESULTS: No effect of testosterone and vardenafil alone was found, but cotreatment of testosterone and vardenafil (PO) caused a significant increase in proceptive and receptive behavior in the sub-primed female rats. Testosterone and vardenafil did not affect fully primed females. ICV administration of vardenafil combined with systemic testosterone, on the other hand, had no effect on sexual activity in both sub-primed and fully primed female rats. CONCLUSIONS: We conclude that cotreatment of subcutaneous testosterone and oral vardenafil increase sexual activity in sub-primed female rats. Our data supports the human finding that combination treatment of testosterone and vardenafil could be used as a new treatment for women with HSDD.

Rat ultrasonic vocalizations and novelty-induced social and non-social investigation behavior in a seminatural environment.

Although rats are known to emit ultrasonic vocalizations (USVs), it remains unclear whether these calls serve an auditory communication purpose. For USVs to be part of communication, the vocal signals will need to be a transfer of information between two or more conspecifics, and with the possibility to induce changes in the behavior of the recipient. Therefore, the aim of our study was to investigate the role of USVs in adult rats' social and non-social investigation strategies when introduced into a large novel environment with unfamiliar conspecifics. We quantified a wide range of social and non-social behaviors in the seminatural environment, which could be affected by subtle signals, including USVs. We found that during the first hour in the seminatural environment the ability to vocalize did not affect how quickly adult rats met each other, their overall social investigation behavior, their passive social behavior nor their aggressive behavior. Furthermore, the non-social exploratory behaviors and behaviors reflecting anxiety/stress-like states were also unaffected. These results demonstrated that a disability to vocalize did not result in significant disadvantages (or changes) compared to intact conspecifics regarding social and non-social behaviors. This suggests that other (multi)sensory cues are more relevant in social interactions than USVs.

The cafeteria diet: A standardized protocol and its effects on behavior.

Obesity is a major health risk, with junk food consumption playing a central role in weight gain, because of its high palatability and high-energy nutrients. The Cafeteria (CAF) diet model for animal experiments consists of the same tasty but unhealthy food products that people eat (e.g. hot dogs and muffins), and considers variety, novelty and secondary food features, such as smell and texture. This model, therefore, mimics human eating patterns better than other models. In this paper, we systematically review studies that have used a CAF diet in behavioral experiments and propose a standardized CAF diet protocol. The proposed diet is ad libitum and voluntary; combines different textures, nutrients and tastes, including salty and sweet products; and it is rotated and varied. Our summary of the behavioral effects of CAF diet show that it alters meal patterns, reduces the hedonic value of other rewards, and tends to reduce stress and spatial memory. So far, no clear effects of CAF diet were found on locomotor activity, impulsivity, coping and social behavior.

Sexual incentive motivation and male and female copulatory behavior in female rats given androgen from postnatal day 20.

Masculinization and feminization of rat sexual behavior has been supposed to occur during a short postnatal period. However, much data have made it evident that these processes may continue until adolescence. In the present study, we evaluated whether androgen treatment of females from postnatal day 20 and onwards could alter sexual motivation and behavior in a male direction. Juveniles were ovariectomized on day 20 and concurrently implanted with Silastic capsules containing either testosterone or dihydrotestosterone. Controls were implanted with an empty capsule. Tests for sexual incentive motivation and male sexual behavior were performed every fifth day when the females were between 50 and 75 days of age. At day 80, a test for female sexual behavior was performed. Females treated with testosterone approached a female sexual incentive far more than a male incentive, showing that sexual motivation had been changed in a male-like direction. Dihydrotestosterone had a similar, albeit smaller, effect. Females implanted with an empty capsule approached both incentives equally. Testosterone produced a high level of mounting behavior, whereas intromission-like behavioral patterns were rare and ejaculation-like behavior was absent. In the test for female sexual behavior, the testosterone-treated animals displayed a relatively high lordosis quotient, far above that displayed in females implanted with dihydrotestosterone or an empty capsule. It is concluded that treatment with an aromatizable androgen during the peripubertal-adolescent period masculinizes sexual motivation and partly sexual behavior. A non-aromatizable androgen weakly masculinize sexual motivation without enhancing male sexual behavior. It appears that simultaneous actions on androgen and estrogen receptors are needed for significant masculinization during the period studied here. Since the testosterone-treated females displayed lordosis, sexual behavior was not defeminized. In sum, these results suggest that sexual differentiation continues well into the peripubertal and adolescent periods.

Silencing and stimulating the medial amygdala impairs ejaculation but not sexual incentive motivation in male rats.

The medial amygdala (MeA) is a sexually dimorphic brain region that integrates sensory information and hormonal signaling, and is involved in the regulation of social behaviors. Lesion studies have shown a role for the MeA in copulation, most prominently in the promotion of ejaculation. The role of the MeA in sexual motivation, but also in temporal patterning of copulation, has not been extensively studied in rats. Here, we investigated the effect of chemogenetic inhibition and stimulation of the MeA on sexual incentive motivation and copulation in sexually experienced male rats. AAV5-CaMKIIa viral vectors coding for Gi, Gq, or no DREADDs (sham) were bilaterally infused into the MeA. Rats were assessed in the sexual incentive motivation test and copulation test upon systemic clozapine N-oxide (CNO) or vehicle administration. We report that MeA stimulation and inhibition did not affect sexual incentive motivation. Moreover, both stimulation and inhibition of the MeA decreased the number of ejaculations in a 30 min copulation test and increased ejaculation latency and the number of mounts and intromissions preceding ejaculation, while leaving the temporal pattern of copulation intact. These results indicate that the MeA may be involved in the processing of sensory feedback required to reach ejaculation threshold. The convergence of the behavioral effects of stimulating as well as inhibiting the MeA may reflect opposing behavioral control of specific neuronal populations within the MeA.

Male rat sexual behavior: Insights from inter-copulatory intervals.

The assessment of sexual behavior in male rats with the aim of unraveling underlying neurobiological mechanisms has in the recent decades been reduced to the annotation of mounts, intromissions and ejaculations. To provide a better understanding of the structure and patterns of copulation, it is necessary to extend and tailor the analysis to the natural organization of male rat copulation. This will lead to better formulation of hypotheses about neurobiological underpinnings of behavior. Mounts and intromissions are naturally organized in mount bouts consisting of one or more copulatory behaviors and are interspersed with time outs. We hypothesized that time outs and the post-ejaculatory interval (inter-copulatory intervals) are related and possibly under the control of a common copulatory inhibition mechanism that is the result of penile sensory stimulation. To test this hypothesis, we analyzed sexual behavior in male rats of three different cohorts from three different laboratories. Results showed that the post-ejaculatory interval and mean time out duration are strongly correlated in all cohorts analyzed. In addition, we showed that individual time out duration is at least partially predicted by the sum of sensory stimulation of copulatory components in the preceding mount bout, with more penile stimulation associated with longer time outs. These findings suggest that both time out and post-ejaculatory interval duration may be determined by the magnitude of sensory stimulation, which inhibits copulation. Whether the same neural pathways are involved in the central orchestration of both time outs and the post-ejaculatory interval should be subject to future studies.

Effects of gonadectomy and dihydrotestosterone on neuronal plasticity in motivation and reward related brain regions in the male rat.

Gonadal hormones affect neuronal morphology to ultimately regulate behaviour. In female rats, oestradiol mediates spine plasticity in hypothalamic and limbic brain structures, contributing to long-lasting effects on motivated behaviour. Parallel effects of androgens in male rats have not been extensively studied. Here, we investigated the effect of both castration and androgen replacement on spine plasticity in the nucleus accumbens shell and core (NAcSh and NAcC), caudate putamen (CPu), medial amygdala (MeA) and medial preoptic nucleus (MPN). Intact and castrated (gonadectomy [GDX]) male rats were treated with dihydrotestosterone (DHT, 1.5 mg) or vehicle (oil) in three experimental groups: intact-oil, GDX-oil and GDX-DHT. Spine density and morphology, measured 24 hours after injection, were determined through three-dimensional reconstruction of confocal z-stacks of DiI-labelled dendritic segments. We found that GDX decreased spine density in the MPN, which was rescued by DHT treatment. DHT also increased spine density in the MeA in GDX animals compared to intact oil-treated animals. By contrast, DHT decreased spine density in the NAcSh compared to GDX males. No effect on spine density was observed in the NAcC or CPu. Spine length and spine head diameter were unaffected by GDX and DHT in the investigated brain regions. In addition, immunohistochemistry revealed that DHT treatment of GDX animals rapidly increased the number of cell bodies in the NAcSh positive for phosphorylated cAMP response-element binding protein, a downstream messenger of the androgen receptor. These findings indicate that androgen signalling plays a role in the regulation of spine plasticity within neurocircuits involved in motivated behaviours.

Effects of perinatal fluoxetine exposure on novelty-induced social and non-social investigation behaviors in a seminatural environment.

Selective serotonin reuptake inhibitors (SSRIs) are increasingly prescribed as medication for various affective disorders during pregnancy. SSRIs cross the placenta and affect serotonergic neurotransmission in the fetus, but the neurobehavioral consequences for the offspring remain largely unclear. Recent rodent research has linked perinatal SSRI exposure to alterations in both social and non-social aspects of behavior. However, this research has mainly focused on behavior within simplified environments. The current study investigates the effects of perinatal SSRI exposure on social and non-social investigation behaviors of adult rat offspring upon introduction to a novel seminatural environment with unknown conspecifics. During the perinatal period (gestational day 1 until postnatal day 21), rat dams received daily treatment with either an SSRI (fluoxetine, 10 mg/kg) or vehicle. Adult male and female offspring were observed within the first hour after introduction to a seminatural environment. The results showed that perinatal fluoxetine exposure altered aspects of non-social investigation behaviors, while not altering social investigation behaviors. More specifically, both fluoxetine-exposed males and females spent more total time on locomotor activity than controls. Furthermore, fluoxetine-exposed females spent less time exploring objects and specific elements in the environment. The data suggest that perinatal exposure to SSRIs leads to a quicker, less detailed investigation strategy in novel environments and that the alteration is mostly pronounced in females.

Serotonin transporter null mutation and sexual behavior in female rats: 5-HT1A receptor desensitization.

INTRODUCTION: Serotonin plays a key role in sexual behavior. In serotonin transporter (SERT) knockout rats (-/-), basal extracellular 5-HT levels are considerably increased, indicating a serotonergic disturbance. Heterozygous SERT(+/-) rats express 50% of SERT in comparison to wild-type rats and may therefore model the s/s phenotype of the human SERT promoter (5-HTTLPR) polymorphism. AIM: In the present study, we used both homozygote and heterozygote SERT knockout and wild-type rats (+/+) to study the putative role of the SERT in female sexual behavior. METHODS: Female rats were brought into estrous by hormonal injections before a paced mating sex test. The effects of the 5-HT(1A)/5-HT(7) receptor agonist (+/-)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (+/-8-OH-DPAT) (0.03-1 mg/kg s.c.) and the 5-HT(1A) receptor antagonist WAY-100635 (0.1-1-mg/kg i.p.) on sexual behaviors of the females were tested separately and in a selected combination of both in all three genotypes. MAIN OUTCOME MEASURES: Proceptive (darting and hopping) and receptive (lordosis) behaviors were quantified. RESULTS: Basal proceptive and receptive sexual activities were not different between SERT+/+, +/- and -/- female rats. The dose-effect curve after +/-8-OH-DPAT for these activities was clearly shifted to the right in SERT-/- animals compared to other genotypes. WAY-100635 alone had no effect on sexual behavior in any genotype, but was able to antagonize the +/-8-OH-DPAT-induced decrease in sexual activities indicating the involvement of the 5-HT(1A) receptor. CONCLUSIONS: The absence (-/-) or reduced (+/-) expression of SERT does not affect basal sexual activity in female rats in a paced mating situation. The data indicate a desensitized 5-HT1A receptor in the SERT-/-, but not in the SERT+/- females. Under normal basal conditions, desensitized 5-HT1A receptors apparently do not play a role in female sexual behavior of the SERT-/-. However, upon activation of the 5-HT1A receptor in "normal" females (SERT+/+ and SERT+/-), a hyposexual behavior is induced.

Female rat sexual behavior is unaffected by perinatal fluoxetine exposure.

Serotonin plays an important role in adult female sexual behavior, however little is known about the influence of serotonin during early development on sexual functioning in adulthood. During early development, serotonin acts as neurotrophic factor, while it functions as a modulatory neurotransmitter in adulthood. The occurrence of serotonin release, could thus have different effects on behavioral outcomes, depending on the developmental period in which serotonin is released. Because serotonin is involved in the development of the HPG axis which is required for puberty establishment, serotonin could also alter expression patterns of for instance the estrogen receptor ɑ (ERɑ). The aim of our study was to investigate the effects of increased serotonin levels during early development on adult female rat sexual behavior during the full behavioral estrus in a seminatural environment. To do so, rats were perinatally exposed with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10 mg/kg FLX) and sexual performance was tested during adulthood. All facets of female sexual behavior between the first and last lordosis (behavioral estrus), and within each copulation bout of the behavioral estrus were analyzed. Besides the length and onset of the behavioral estrus and the sexual behaviors patterns, other social and conflict behavior were also investigated. In addition, we studied the effects of perinatal FLX exposure on ERɑ expression patterns in the medial preoptic nucleus, ventromedial nucleus of the hypothalamus, medial amygdala, bed nucleus of the stria terminalis, and the dorsal raphé nucleus. The results showed that perinatal fluoxetine exposure has no effect on adult female sexual behavior. The behavioral estrus of FLX-females had the same length and pattern as CTR-females. In addition, FLX- and CTR-females showed the same amount of paracopulatory behavior and lordosis, both during the full behavioral estrus and the "most active bout". Furthermore, no differences were found in the display of social and conflict behaviors, nor in ERɑ expression patterns in the brain. We conclude that increases in serotonin levels during early development do not have long-term consequences for female sexual behavior in adulthood.

Third-party prosocial behavior in adult female rats is impaired after perinatal fluoxetine exposure.

SSRIs are commonly used to treat pregnant women with depression. However, SSRIs can cross the placenta and affect the development of the fetus. The effects of perinatal SSRI exposure, and especially the effects on social behavior, are still incompletely documented. This study first aims to investigate whether rats show prosocial behavior in the form of consolation behavior. Secondly, it aims to investigate whether perinatal SSRI exposure affects this prosocial behavior. At last, we investigate whether the behavior changed after the rats had been exposed to an additional white-noise stressor. Rat dams received 10 mg/kg/d fluoxetine (FLX) or vehicle (CTR) via oral gavage from gestational day 1 until postnatal day 21. At adulthood, the rat offspring were housed in four cohorts of 4 females and 4 males in a seminatural environment. As prosocial behaviors are more prominent after stressful situations, we investigated the behavioral response of rats immediately after natural aggressive encounters (fights). Additionally, we studied whether a stressful white-noise exposure would alter this response to the aggressive encounters. Our study indicates that CTR-female rats are able to show third party prosocial behavior in response to witnessing aggressive encounters between conspecifics in a seminatural environment. In addition, we showed that perinatal FLX exposure impairs the display of prosocial behavior in female rats. Moreover, we found no signs of prosocial behavior in CTR- and FLX-males after natural aggressive encounters. After white-noise exposure the effects in third party prosocial behavior of CTR-females ceased to exist. We conclude that female rats are able to show prosocial behavior, possibly in the form of consolation behavior. In addition, the negative effects of perinatal fluoxetine exposure on prosocial behavior could provide additional evidence that SSRI treatment during pregnancy could contribute to the risk for social impairments in the offspring.

Female Reproductive Behavior.

Reproductive behavior is the behavior related to the production of offspring and includes all aspects from the establishment of mating systems, courtship, sexual behavior, and parturition to the care of young. In this chapter, I outline the hormonal regulation of the estrous cycle, followed by a description of the neural regulation of female sexual behavior. Ovarian hormones play an important role in the induction of ovulation and behavioral estrus, in which they interact closely with several neurotransmitters and neuropeptides to induce sexual behavior. This chapter discusses the latest research on the role of estrogen, progesterone, serotonin, dopamine, noradrenaline, oxytocin, and GABA in female mating behavior. In addition, the most relevant brain areas, such as the preoptic area and the ventromedial nucleus of the hypothalamus, in which these regulations take place, are discussed.

Perinatal fluoxetine exposure changes social and stress-coping behavior in adult rats housed in a seminatural environment.

The use of selective serotonin reuptake inhibitors (SSRI) during pregnancy has increased tremendously, but the consequences for the offspring remain largely unclear. Several studies have described potential effects of perinatal SSRI-exposure on neurobehavioral outcomes using simplified rodent test set-ups, however these set-ups only assess a small fraction of the behavior. For translational purposes it is important to take the environmental influences into account which children are exposed to in real life. By using a seminatural environmental set-up, this study is the first to assess behavioral outcomes in offspring exposed to perinatal SSRI exposure under seminatural circumstances. Mothers received daily the SSRI fluoxetine (FLX, 10 mg/kg p.o.) or vehicle (CTR) from gestational day 1 until postnatal day 21. To assess the effect of FLX exposure during early development, female and male offspring were behaviorally tested in the seminatural environment at adulthood. Baseline behavior was measured in addition to responses during and after stressful white-noise events. Behavior was observed on two days, day 4 on which females were sexually non-receptive, and day 7, on which females were sexual receptive. Perinatal FLX exposure reduced general activity in females and increased behavior related to a social context in both males and females. After a stressful white-noise event some behaviors switched. Whereas FLX-females switch from resting socially to resting more solitarily, FLX-males show an increase in self-grooming behavior after the stressor and showed more freezing behavior in the open area. We conclude that perinatal FLX exposure leads to alterations in social and stress-coping behaviors in adulthood, when observed in a seminatural environment. Whether these adaptations in behavior are advantageous or disadvantageous remains to be established.

Translational research into sexual disorders: pharmacology and genomics.

The existence of sexual dysfunctions in men, including premature and retarded ejaculation poses challenges to develop translational models in rats that may help in improving treatment and delineate the neural mechanisms of action. Most of our current understanding of the neurobiology, neuroanatomy and psychopharmacology of sexual behavior and ejaculatory function has been derived from preclinical studies in the rat. When large populations of male rats are tested on sexual activity during four successive tests, over time individual rats display a very stable sexual behavior that is either slow, normal or fast as characterized by the number of ejaculations performed. These sexual endophenotypes are postulated as rat counterparts of premature (fast rats) or retarded ejaculation (slow rats). Psychopharmacology in these endophenotypes may help to delineate the underlying mechanisms and pathology. This is illustrated by the effects of serotonergic antidepressants and serotonergic compounds on sexual and ejaculatory behavior of rats. Further unravelling of sexual endophenotypes may benefit from the use of chromosomal substitution strains in mice that enable the localization of relevant chromosomal areas and genes involved in ejaculation processes. These preclinical studies and models contribute to a better understanding of the neurobiology of ejaculation and boost the development of novel drug targets to treat ejaculatory disorders such as premature and retarded ejaculation.

Mate choice could be random in female rats (Rattus norvegicus).

Female mate choice is often investigated in terms of reproductive success in order to understand how male characteristics contribute to sexual attractiveness. Previous studies have found that females rats prefer mating with their first encounter rather than males visited subsequently, suggesting that the rewarding value of this first encounter is enough to reinforce mating with the first partner. Using a multiple chambers paradigm, we allowed female rats to copulate freely with three males placed each in a different chamber. Then, we switched the males' position, and let the female interact with them freely again within the same session. We tested whether female mate choice was relying rather on a preferred male rat or on a preferred mating location. The results showed that females spent most time with the male in the chamber of 1st entry in the beginning, but as soon as male rats switched chambers, the female rat continued to copulate with the new male in the same chamber of 1st entry, instead of mating with her previously preferred male rat. This suggests that the male preference is an artefact of location preference. Therefore, female mate choice seems to be rather random than the consequence of an individual choice based on male characteristics. This finding, although contradictory with the intuitive feeling that mate choice is a crucial feature in sexual and reproductive behavior, is supported by several recent observations. In the coming years, behavioral neuroscience should bring light to the brain processes at work in random mate choice.