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

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00213-021-05984-8

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.</p

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

Assessment of sexual behavior in rats: the potentials and pitfalls

In the field of behavioral neuroscience, it is essential to use the appropriate animal models for the topic of investigation. Using the wrong model can result in false interpretation of the results. In this review we will discuss the animal models used to study sexual behavior, with a focus on rats. We will discuss the potentials and pitfalls of the different paradigms and try to make recommendations on how research in this field could be optimized. Both male and female sexual behavior are discussed, in addition to sexual motivation

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