Chronic oxytocin-driven alternative splicing of Crfr2α induces anxiety.

The neuropeptide oxytocin (OXT) has generated considerable interest as potential treatment for psychiatric disorders, including anxiety and autism spectrum disorders. However, the behavioral and molecular consequences associated with chronic OXT treatment and chronic receptor (OXTR) activation have scarcely been studied, despite the potential therapeutic long-term use of intranasal OXT. Here, we reveal that chronic OXT treatment over two weeks increased anxiety-like behavior in rats, with higher sensitivity in females, contrasting the well-known anxiolytic effect of acute OXT. The increase in anxiety was transient and waned 5 days after the infusion has ended. The behavioral effects of chronic OXT were paralleled by activation of an intracellular signaling pathway, which ultimately led to alternative splicing of hypothalamic corticotropin-releasing factor receptor 2α (Crfr2α), an important modulator of anxiety. In detail, chronic OXT shifted the splicing ratio from the anxiolytic membrane-bound (mCRFR2α) form of CRFR2α towards the soluble CRFR2α (sCRFR2α) form. Experimental induction of alternative splicing mimicked the anxiogenic effects of chronic OXT, while sCRFR2α-knock down reduced anxiety-related behavior of male rats. Furthermore, chronic OXT treatment triggered the release of sCRFR2α into the cerebrospinal fluid with sCRFR2α levels positively correlating with anxiety-like behavior. In summary, we revealed that the shifted splicing ratio towards expression of the anxiogenic sCRFR2α underlies the adverse effects of chronic OXT treatment on anxiety.

Microglia react to partner loss in a sex- and brain site-specific manner in prairie voles.

Positive social relationships are paramount for the survival of mammals and beneficial for mental and physical health, buffer against stressors, and even promote appropriate immune system functioning. By contrast, impaired social relationships, social isolation, or the loss of a bonded partner lead to aggravated physical and mental health. For example, in humans partner loss is detrimental for the functioning of the immune system and heightens the susceptibility for the development of post-traumatic stress disorders, anxiety disorders, and major depressive disorders. To understand potential underlying mechanisms, the monogamous prairie vole can provide important insights. In the present study, we separated pair bonded male and female prairie voles after five days of co-housing, subjected them to the forced swim test on the fourth day following separation, and studied their microglia morphology and activation in specific brain regions. Partner loss increased passive stress-coping in male, but not female, prairie voles. Moreover, partner loss was associated with microglial priming within the parvocellular region of the paraventricular nucleus of the hypothalamus (PVN) in male prairie voles, whereas in female prairie voles the morphological activation within the whole PVN and the prelimbic cortex (PrL) was decreased, marked by a shift towards ramified microglial morphology. Expression of the immediate early protein c-Fos following partner loss was changed within the PrL of male, but not female, prairie voles. However, the loss of a partner did not affect the investigated aspects of the peripheral immune response. These data suggest a potential sex-dependent mechanism for the regulation of microglial activity following the loss of a partner, which might contribute to the observed differences in passive stress-coping. This study furthers our understanding of the effects of partner loss and its short-term impact on the CNS as well as the CNS immune system and the peripheral innate immune system in both male and female prairie voles.

Mom doesn't care: When increased brain CRF system activity leads to maternal neglect in rodents.

Mothers are the primary caregivers in mammals, ensuring their offspring's survival. This strongly depends on the adequate expression of maternal behavior, which is the result of a concerted action of "pro-maternal" versus "anti-maternal" neuromodulators such as the oxytocin and corticotropin-releasing factor (CRF) systems, respectively. When essential peripartum adaptations fail, the CRF system has negative physiological, emotional and behavioral consequences for both mother and offspring often resulting in maternal neglect. Here, we provide an elaborate and unprecedented review on the implications of the CRF system in the maternal brain. Studies in rodents have advanced our understanding of the specific roles of brain regions such as the limbic bed nucleus of the stria terminalis, medial preoptic area and lateral septum even in a CRF receptor subtype-specific manner. Furthermore, we discuss potential interactions of the CRF system with other neurotransmitters like oxytocin and noradrenaline, and present valuable translational aspects of the recent research.

When mothers neglect their offspring: an activated CRF system in the BNST is detrimental for maternal behavior.

Becoming a mother is an intense experience that not only changes a woman's life but is also paralleled by multiple central adaptations. These changes evolve before parturition and continue to persist into lactation, thereby ensuring the full commitment of the mother to care for the newborns. Most of our knowledge on these adaptations that drive the peripartum brain come from rodent animal models. On one side, it is known that maternal behavior is initiated and maternal mood is stabilized by an upregulation of the pro-maternal neuropeptide systems' activity of oxytocin and arginine-vasopressin. On the other side, signaling of the rather anti-maternal corticotropin-releasing factor system triggers maternal neglect and increases maternal anxiety. Here, we discuss how the corticotropin-releasing factor system based in the limbic bed nucleus of the stria terminalis negatively affects maternal behavior and maternal mood. Moreover, we apply microdialysis and acute pharmacological interventions to demonstrate how the corticotropin-releasing factor system potentially interacts with the pro-maternal oxytocin system in the posterior bed nucleus of the stria terminalis to trigger certain aspects of maternal behavior.

Brain CRF-binding protein modulates aspects of maternal behavior under stressful conditions and supports a hypo-anxious state in lactating rats.

Reduced corticotropin-releasing factor (CRF) receptor activation in the postpartum period is essential for adequate maternal behavior. One of the factors contributing to this hypo-activity might be the CRF-binding protein (CRF-BP), which likely reduces the availability of free extracellular CRF/urocortin 1. Here, we investigated behavioral effects of acute CRF-BP inhibition using 5µg of CRF(6-33) administered either centrally or locally within different parts of the bed nucleus of the stria terminalis (BNST) in lactating rats. Additionally, we assessed CRF-BP expression in the BNST comparing virgin and lactating rats. Central CRF-BP inhibition increased maternal aggression during maternal defense but did not affect maternal care or anxiety-related behavior. CRF-BP inhibition in the medial-posterior BNST had no effect on maternal care under non-stress conditions but impaired the reinstatement of maternal care following stressor exposure. Furthermore, maternal aggression, particularly threat behavior, and anxiety-related behavior were elevated by CRF-BP inhibition in the medial-posterior BNST. In the anterior-dorsal BNST, CRF-BP inhibition increased only non-maternal behaviors following stress. Finally, CRF-BP expression was higher in the anterior compared to the posterior BNST but was not different between virgin and lactating rats in either region. Our study demonstrates a key role of the CRF-BP, particularly within the BNST, in modulating CRF's impact on maternal behavior. The CRF-BP is important for the reinstatement of maternal care after stress, for modulating threat behavior during an aggressive encounter and for maintaining a hypo-anxious state during lactation. Thus, the CRF-BP likely contributes to the postpartum-associated down-regulation of the CRF system in a brain region-dependent manner.

Antagonism of V1b receptors promotes maternal motivation to retrieve pups in the MPOA and impairs pup-directed behavior during maternal defense in the mpBNST of lactating rats.

Recent studies using V1b receptor (V1bR) knockout mice or central pharmacological manipulations in lactating rats highlighted the influence of this receptor for maternal behavior. However, its role in specific brain sites known to be important for maternal behavior has not been investigated to date. In the present study, we reveal that V1bR mRNA (qPCR) and protein levels (Western blot) within either the medial preoptic area (MPOA) or the medial-posterior part of the bed nucleus of the stria terminalis (mpBNST) did not differ between virgin and lactating rats. Furthermore, we characterized the effects of V1bR blockade via bilateral injections of the receptor subtype-specific antagonist SSR149415 within the MPOA or the mpBNST on maternal behavior (maternal care under non-stress and stress conditions, maternal motivation to retrieve pups in a novel environment, maternal aggression) and anxiety-related behavior in lactating rats. Blocking V1bR within the MPOA increased pup retrieval, whereas within the mpBNST it decreased pup-directed behavior, specifically licking/grooming the pups, during the maternal defense test. In addition, immediately after termination of the maternal defense test, V1bR antagonism in both brain regions reduced nursing, particularly arched back nursing. Anxiety-related behavior was not affected by V1bR antagonism in either brain region. In conclusion our data indicate that V1bR antagonism significantly modulates different aspects of maternal behavior in a brain region-dependent manner.

Hypoactivation of CRF receptors, predominantly type 2, in the medial-posterior BNST is vital for adequate maternal behavior in lactating rats.

Maternal behavior ensures the proper development of the offspring. In lactating mammals, maternal behavior is impaired by stress, the physiological consequence of central corticotropin-releasing factor receptor (CRF-R) activation. However, which CRF-R subtype in which specific brain area(s) mediates this effect is unknown. Here we confirmed that an intracerebroventricularly injected nonselective CRF-R antagonist enhances, whereas an agonist impairs, maternal care. The agonist also prolonged the stress-induced decrease in nursing, reduced maternal aggression and increased anxiety-related behavior. Focusing on the bed nucleus of the stria terminalis (BNST), CRF-R1 and CRF-R2 mRNA expression did not differ in virgin versus lactating rats. However, CRF-R2 mRNA was more abundant in the posterior than in the medial BNST. Pharmacological manipulations within the medial-posterior BNST showed that both CRF-R1 and CRF-R2 agonists reduced arched back nursing (ABN) rapidly and after a delay, respectively. After stress, both antagonists prevented the stress-induced decrease in nursing, with the CRF-R2 antagonist actually increasing ABN. During the maternal defense test, maternal aggression was abolished by the CRF-R2, but not the CRF-R1, agonist. Anxiety-related behavior was increased by the CRF-R1 agonist and reduced by both antagonists. Both antagonists were also effective in virgin females but not in males, revealing a sexual dimorphism in the regulation of anxiety within the medial-posterior BNST. In conclusion, the detrimental effects of increased CRF-R activation on maternal behavior are mediated via CRF-R2 and, to a lesser extent, via CRF-R1 in the medial-posterior BNST in lactating rats. Moreover, both CRF-R1 and CRF-R2 regulate anxiety in females independently of their reproductive status.

CRF binding protein activity in the hypothalamic paraventricular nucleus is essential for stress adaptations and normal maternal behaviour in lactating rats.

To ensure the unrestricted expression of maternal behaviour peripartum, activity of the corticotropin-releasing factor (CRF) system needs to be minimised. CRF binding protein (CRF-BP) might be crucial for this adaptation, as its primary function is to sequester freely available CRF and urocortin1, thereby dampening CRF receptor (CRF-R) signalling. So far, the role of CRF-BP in the maternal brain has barely been studied, and a potential role in curtailing activation of the stress axis is unknown. We studied gene expression for CRF-BP and both CRF-R within the paraventricular nucleus (PVN) of the hypothalamus. In lactating rats, Crh-bp expression in the parvocellular PVN was significantly higher and Crh-r1 expression in the PVN significantly lower compared to virgin rats. Acute CRF-BP inhibition in the PVN with infusion of CRF(6-33) increased basal plasma corticosterone concentrations under unstressed conditions in dams. Furthermore, while acute intra-PVN infusion of CRF increased corticosterone secretion in virgin rats, it was ineffective in vehicle (VEH)-pre-treated lactating rats, probably due to a buffering effect of CRF-BP. Indeed, pre-treatment with CRF(6-33) reinstated a corticosterone response to CRF in lactating rats, highlighting the critical role of CRF-BP in maintaining attenuated stress reactivity in lactation. To our knowledge, this is the first study linking hypothalamic CRF-BP activity to hypothalamic-pituitary-adrenal axis regulation in lactation. In terms of behaviour, acute CRF-BP inhibition in the PVN under non-stress conditions reduced blanket nursing 60 min and licking/grooming 90 min after infusion compared to VEH-treated rats, while increasing maternal aggression towards an intruder. Lastly, chronic intra-PVN inhibition of CRF-BP strongly reduced maternal aggression, with modest effects on maternal motivation and care. Taken together, intact activity of the CRF-BP in the PVN during the postpartum period is essential for the dampened responsiveness of the stress axis, as well as for the full expression of appropriate maternal behaviour.

Reduced brain corticotropin-releasing factor receptor activation is required for adequate maternal care and maternal aggression in lactating rats.

The brain corticotropin-releasing factor (CRF) system triggers a variety of neuroendocrine and behavioural responses to stress. Whether maternal behaviour and emotionality in lactation are modulated by CRF has rarely been investigated. In the present study, we measured CRF mRNA expression within the parvocellular part of the paraventricular nucleus in virgin and lactating Wistar rats bred for high (HAB) and low (LAB) anxiety-related behaviour or non-selected for anxiety (NAB). Further, we intracerebroventricularly infused synthetic CRF or the CRF receptor (CRF-R) antagonist D-Phe to manipulate CRF-R1/2 non-specifically in lactating HAB, LAB, and NAB dams, and monitored maternal care, maternal motivation, maternal aggression, and anxiety. The CRF mRNA expression in the parvocellular part of the paraventricular nucleus was higher in HAB vs. LAB rats independent of reproductive status. The lactation-specific decrease of CRF mRNA was confirmed in LAB and NAB dams but was absent in HAB dams. Intracerebroventricular CRF decreased maternal care under basal conditions in the home cage in all breeding lines and reduced attack behaviour in HAB and LAB dams during maternal defence. In contrast, D-Phe rescued maternal care after exposure to maternal defence in the home cage without influencing maternal aggression. Furthermore, D-Phe decreased and CRF tended to increase anxiety in HAB/NAB and LAB dams, respectively, suggesting an anxiogenic effect of CRF in lactating females. In conclusion, low CRF-R activation during lactation is an essential prerequisite for the adequate occurrence of maternal behaviour.

Brief versus long maternal separation in lactating rats: Consequences on maternal behavior, emotionality, and brain oxytocin receptor binding.

Maternal separation is a widely used animal model to study early life adversity in offspring. However, only a few studies have focused on the impact of disrupting the maternal bond from the mother's perspective. Such studies reveal alterations in behavior, whereas the underlying neuroendocrine mechanisms remain largely unknown. In this study, we compared the consequences of daily brief maternal separation (BMS; 15 min) versus long maternal separation (LMS; 180 min) during the first week postpartum with respect to behavioral and neuroendocrine changes in lactating Sprague-Dawley dams. Mothers were tested for their maternal care before and after separation, maternal motivation to retrieve pups, as well as anxiety-related and stress-coping behaviors. In addition, we analyzed their basal plasma corticosterone levels and oxytocin receptor binding in selected brain regions of the limbic system and maternal network. LMS dams showed higher levels of behavioral alterations compared to BMS and non-maternally separated (NMS) dams, including increased licking and grooming of the pups and decreased maternal motivation. Anxiety-related behavior was not affected by either separation paradigm, whereas passive stress-coping behavior tended to increase in the LMS group. Plasma corticosterone concentrations were not different between groups. Oxytocin receptor binding was higher in the medial preoptic area and tended to be higher in the prelimbic cortex of LMS dams, only. Our results demonstrate that especially daily prolonged maternal separation impacts on the mothers' behavior and oxytocin system, which suggests that enhanced oxytocin receptor binding could be a compensatory mechanism for potentially decreased central oxytocin release due to limited pup contact.

Selective breeding of rats for high (HAB) and low (LAB) anxiety-related behaviour: A unique model for comorbid depression and social dysfunctions.

Animal models of selective breeding for extremes in emotionality are a strong experimental approach to model psychopathologies. They became indispensable in order to increase our understanding of neurobiological, genetic, epigenetic, hormonal, and environmental mechanisms contributing to anxiety disorders and their association with depressive symptoms or social deficits. In the present review, we extensively discuss Wistar rats selectively bred for high (HAB) and low (LAB) anxiety-related behaviour on the elevated plus-maze. After 30 years of breeding, we can confirm the prominent differences between HAB and LAB rats in trait anxiety, which are accompanied by consistent differences in depressive-like, social and cognitive behaviours. We can further confirm a single nucleotide polymorphism in the vasopressin promotor of HAB rats causative for neuropeptide overexpression, and show that low (or high) anxiety and fear levels are unlikely due to visual dysfunctions. Thus, HAB and LAB rats continue to exist as a reliable tool to study the multiple facets underlying the pathology of high trait anxiety and its comorbidity with depression-like behaviour and social dysfunctions.

Both oxytocin and vasopressin are mediators of maternal care and aggression in rodents: from central release to sites of action.

In the mammalian peripartum period, the activity of both the brain oxytocin and vasopressin system is elevated as part of the physiological adaptations occurring in the mother. This is reflected by increased expression and intracerebral release of oxytocin and vasopressin, as well as increased neuropeptide receptor expression and binding. In this review we discuss the functional role of the brain oxytocin and vasopressin system in the context of maternal behavior, specifically maternal care and maternal aggression in rodents. In order to enable the identification of significant and peptide-specific contributions to the display of maternal behavior, various complementary animal models of maternal care and/or maternal aggression were studied, including rats selectively bred for differences in anxiety-related behavior (HAB and LAB dams), monitoring of local neuropeptide release during ongoing maternal behavior, and local pharmacological or genetic manipulations of the neuropeptide systems. The medial preoptic area was identified as a major site for oxytocin- and vasopressin-mediated maternal care. Furthermore, both oxytocin and vasopressin release and receptor activation in the central amygdala and the bed nucleus of the stria terminalis play an important role for maternal aggression. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

Dysfunctions of brain oxytocin signaling: Implications for poor mothering.

Good mothering has profound impact on both the mother's and the young's well-being. Consequently, experiencing inadequate maternal care - or even neglect - in the first stages of life is a major risk factor for the development of psychiatric disorders, and even for poor parenting towards the future offspring. Thus, understanding the neurobiological basis of maternal neglect becomes crucial. Along with other neurotransmitters and neuropeptides, oxytocin (OXT) has long been known as one of the main modulators of maternal behavior. In rodents, disruptions of central OXT transmission have been associated with poor maternal responses, like impaired onset of nursing behaviors, and reduced care and defense of the pups. Importantly, such behavioral and molecular deficits can be transmitted through generations, creating a vicious circle of low-quality maternal behavior. Similarly, evidence from human studies shows that OXT signaling is defective in conditions of inadequate mothering and child neglect. On those premises, this review aims at providing a comprehensive overview of animal and human studies linking perturbed OXT transmission to poor maternal behavior. Considering the important fallouts of inadequate maternal responses, we believe that unraveling the alterations in OXT transmission might provide useful insights for a better understanding of maternal neglect and, ultimately, for future intervention approaches.

Maternal nurturing is dependent on her innate anxiety: the behavioral roles of brain oxytocin and vasopressin.

The maternal brain undergoes remarkable physiological and behavioral changes in the peripartum period to meet the demands of the offspring. Here, the brain neuropeptides oxytocin and vasopressin, together with prolactin, play important roles. These neuropeptides are critically involved in the regulation of maternal behavior. Furthermore, reduced anxiety in lactation is another adaptation of the maternal brain. Therefore, a link between maternal behavior and maternal anxiety has been repeatedly postulated. This is supported by our studies in rats bred for high (HAB) and low (LAB) anxiety-related behavior. While female HAB rats become less anxious in lactation, their anxiety level is still four times higher compared with LAB dams. Interestingly, HAB dams display an intense and protective mothering style including increased arched back nursing and pup retrieval whereas LAB dams display only low levels of maternal care. The amount of maternal care directed towards the pups correlates with the mother's innate anxiety. In addition to differences in maternal care, HAB dams are also more protective as they show heightened aggression against a virgin intruder compared with the less aggressive LAB dams. The level of maternal aggression correlates with both their innate anxiety level as well as with the release of oxytocin and vasopressin in hypothalamic and limbic brain areas. Importantly, manipulations of the brain oxytocin and vasopressin systems alter maternal behavior and - depending on the brain region - can also alter the dam's anxiety. Thus, the mother's innate anxiety determines her maternal performance and oxytocin and vasopressin are involved in both parameters.

Brain vasopressin is an important regulator of maternal behavior independent of dams' trait anxiety.

The neuropeptide arginine vasopressin (AVP) is arguably among the most potent regulators of social behaviors in mammals identified to date. However, only the related neuropeptide oxytocin (OXT) has been shown to promote maternal behavior. Here, we assess the role of AVP in maternal care, in particular in arched back nursing, pup retrieval, and pup contact by using complementary pharmacological and genetic approaches. Also, experiments were performed in rat dams with differences in trait anxiety, i.e., rats bred for either high (HAB) or low (LAB) anxiety-related behavior as well as nonselected (NAB) dams. Viral vector-mediated up-regulation of AVP V1a receptors (AVP-Rs) within the medial preoptic area of lactating NAB rats and chronic central AVP treatment of NAB and LAB dams improved, whereas local blockade of AVP-R expression by means of antisense oligodeoxynucleotides or central AVP-R antagonism impaired, maternal care in NAB dams. Also, in HAB rats with a genetically determined elevated brain AVP activity, intrinsically high levels of maternal care were reversed by blockade of AVP-R actions. Treatment-induced impairment of AVP-mediated maternal behavior increased adult emotionality and impaired social interactions in male offspring of NAB dams. These findings provide direct evidence for an essential and highly potent role of brain AVP in promoting maternal behavior, which seems to be independent of the dam's trait anxiety.

The brain oxytocin and corticotropin-releasing factor systems in grieving mothers: What we know and what we need to learn.

The bond between a mother and her child is the strongest bond in nature. Consequently, the loss of a child is one of the most stressful and traumatic life events that causes Prolonged Grief Disorder in up to 94 % of bereaved parents. While both parents are affected, mothers are of higher risk to develop mental health complications; yet, very little research has been done to understand the impact of the loss of a child, stillbirth and pregnancy loss on key neurobiological systems. The emotional impact of losing a child, e.g., Prolonged Grief Disorder, is likely accompanied by dysregulations in neural systems important for mental health. Among those are the neuropeptides contributing to attachment and stress processing. In this review, we present evidence for the involvement of the brain oxytocin (OXT) and corticotropin-releasing factor (CRF) systems, which both play a role in maternal behavior and the stress response, in the neurobiology of grief in mothers from a behavioral and molecular point of view. We will draw conclusions from reviewing relevant animal and human studies. However, the paucity of research on the tragic end to an integral bond in a female's life calls for the need and responsibility to conduct further studies on mothers experiencing the loss of a child both in the clinic and in appropriate animal models.

Oxytocin and vasopressin within the ventral and dorsal lateral septum modulate aggression in female rats.

In contrast to male rats, aggression in virgin female rats has been rarely studied. Here, we established a rat model of enhanced aggression in females using a combination of social isolation and aggression-training to specifically investigate the involvement of the oxytocin (OXT) and arginine vasopressin (AVP) systems within the lateral septum (LS). Using neuropharmacological, optogenetic, chemogenetic as well as microdialysis approaches, we revealed that enhanced OXT release within the ventral LS (vLS), combined with reduced AVP release within the dorsal LS (dLS), is required for aggression in female rats. Accordingly, increased activity of putative OXT receptor-positive neurons in the vLS, and decreased activity of putative AVP receptor-positive neurons in the dLS, are likely to underly aggression in female rats. Finally, in vitro activation of OXT receptors in the vLS increased tonic GABAergic inhibition of dLS neurons. Overall, our data suggest a model showing that septal release of OXT and AVP differentially affects aggression in females by modulating the inhibitory tone within LS sub-networks.

Vasopressin released within the central amygdala promotes maternal aggression.

Vasopressin regulates important aspects of social behaviour. Although vasopressin is more prominent in the expression of male social behaviours, we recently demonstrated its role in the fine-tuned maintenance of maternal care in lactating rats. Here, we investigate the involvement of brain vasopressin in the regulation of maternal aggression in lactating Wistar rats selectively bred for either high (HAB) or low (LAB) anxiety-related behaviour. The genetically determined elevation in vasopressin mRNA expression was confirmed within the hypothalamic paraventricular nucleus of virgin and lactating HAB rats and was additionally found in limbic brain areas. Lactating HAB dams are more maternally aggressive as part of their generally higher level of maternal care compared with LAB rats. Using intracerebral microdialysis, we describe increased vasopressin release within the central amygdala, but not the paraventricular nucleus, during maternal aggression only in HAB dams. Moreover, the release of vasopressin within the central amygdala was positively correlated with the display of offensive behaviour. Blockade of local vasopressin actions by bilateral administration of a selective vasopressin V1a receptor antagonist into the central amygdala reduced maternal aggression in HAB dams, whereas synthetic vasopressin increased the low level of aggression in LAB rats. Vasopressin receptor binding within the central amygdala or the paraventricular nucleus was similar in HAB and LAB females. In conclusion, vasopressin is an important neuropeptide regulating maternal aggressive behaviour, thus further extending its involvement in female social behaviour. Differences in intracerebral vasopressin release within the central amygdala rather than local vasopressin receptor binding contribute to the level of maternal aggression.

Attenuation of the neuronal stress responsiveness and corticotrophin releasing hormone synthesis after sexual activity in male rats.

Beneficial effects of sexual activity and mating on the responsiveness to environmental stress can be observed in humans and other mammalian species alike, but the underlying neurobiological mechanisms are largely unknown. Sexual activity and mating with a receptive female has recently been shown to reduce the subsequent emotional stress response via activation of the brain oxytocin system. Therefore, we investigated the neuronal and hormonal responses to an acute stressor (forced swimming) after mating in male rats. Attenuation of the stress-induced increase of c-fos and CRH mRNA expression within the hypothalamic paraventricular nucleus 4 h after mating revealed that sexual activity reduced neuronal reactivity in this region. However, this effect was independent of oxytocin as oxytocin receptor blockade, by central administration of an oxytocin receptor antagonist, after mating did not prevent the reduced expression of c-fos mRNA in response to stressor exposure. Mating itself stimulated corticotrophin (ACTH) and corticosterone secretion, which was absent in males after contact with an unreceptive female (non-mated group). However, ACTH and corticosterone responses to forced swimming applied either 45 min or 4 h after female contact were similar between mated and non-mated males. These findings provide evidence for a stress-protective effect of sexual activity and mating in male rats and for dissociation between neuronal and neuroendocrine stress responses.