The neuropeptide oxytocin (OT) modulates social behaviours and is an important anxiolytic substance of the brain. However, sites of action and the intracellular signalling pathways downstream of OT receptors (OTR) within the brain remain largely unknown. In the present studies, we localized the anxiolytic effect of OT by bilateral microinfusion of OT (0.01 nmol/0.5 microL) into the hypothalamic paraventricular nucleus (PVN) in male rats using both the elevated plus-maze and the light-dark box. Moreover, intracerebroventricular administration of OT, but not of the related neuropeptide vasopressin (VP), dose-dependently activated the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade. Specifically, OT induced the phosphorylation of Raf-1, MEK1/2 and ERK1/2 in the hypothalamus in vivo and in hypothalamic H32 neurons via EGF receptors. OT-induced ERK1/2 phosphorylation was immunohistochemically localized within VP neurons of the PVN and the supraoptic nucleus. Importantly, the anxiolytic effect of OT within the PVN was prevented by local inhibition of the MAP kinase cascade with a MEK1/2 inhibitor (U0126, 0.5 nmol/0.5 microL) locally infused prior to OT, indicating the causal involvement of this intracellular signalling cascade in the behavioural effect of OT. OT effects within the hypothalamus may have far-reaching implications for the regulation of emotionality and social behaviours and, consequently, for the development of possible therapeutic strategies to treat affective disorders. Thus, OTR agonism or activation of the ERK1/2 cascade, specifically within the hypothalamus, may provide therapeutically relevant mechanisms.

Sexual activity and mating are accompanied by a high level of arousal, whereas anecdotal and experimental evidence demonstrate that sedation and calmness are common phenomena in the postcoital period in humans. These remarkable behavioral consequences of sexual activity contribute to a general feeling of well being, but underlying neurobiological mechanisms are largely unknown. Here, we demonstrate that sexual activity and mating with a receptive female reduce the level of anxiety and increase risk-taking behavior in male rats for several hours. The neuropeptide oxytocin has been shown to exert multiple functions in male and female reproduction, and to play a key role in the regulation of emotionality after its peripheral and central release, respectively. In the present study, we reveal that oxytocin is released within the brain, specifically within the hypothalamic paraventricular nucleus, of male rats during mating with a receptive female. Furthermore, blockade of the activated brain oxytocin system by central administration of an oxytocin receptor antagonist immediately after mating prevents the anxiolytic effect of mating, while having no effect in nonmated males. These findings provide direct evidence for an essential role of an activated brain oxytocin system mediating the anxiolytic effect of mating in males.black-white box ͉ elevated plus maze ͉ paraventricular nucleus ͉ risk-taking behavior ͉ anxiety T he neuropeptide oxytocin (OT) is a well acknowledged neuromodulator/neurotransmitter of the brain regulating emotionality, stress coping, and prosocial behaviors (1-3). In females, high activity of the brain OT system has been linked to the fine-tuned regulation of parturition and milk letdown (4), to the performance of maternal behaviors (3), and to the low stress response characteristic for the peripartum period (5, 6). Importantly, behavioral and physiological actions of intracerebral OT are not limited to females, because OT synthesis, local OT release, and OT receptor binding have also been demonstrated in the male brain (2, 7, 8). A major site of both OT synthesis and release within the brain is the hypothalamic paraventricular nucleus (PVN) (2), a region integrating behavioral and neuroendocrine stress responses (9). In male rats and mice, OT is an important regulator of sexual function (10), of anxiety (11), and of stress-coping circuitries (12)(13)(14). Moreover, in humans, intranasal OT was recently described to promote trust (15), and to reduce the level of anxiety (16), possibly at the level of the amygdala (17). With respect to sexual activity, preclinical (18) and human (19) research has shown elevated OT secretion into the blood during mating behavior and orgasm, respectively. Additionally, increased OT levels have been described in the cerebrospinal fluid after mating in rats (20), which is indicative of stimulation of the OT system (21).In combination, these findings lead us to hypothesize that mating results in reduced anxiety-related behavior, possibly mediated by an elevation in local...

Sexual activity and partner intimacy results in several positive consequences in the context of stress-coping, both in males and females, such as reduced state anxiety in male rats after successful mating. However, in female rats, mating is a rewarding experience only when the estrous female is able to control sexual interactions, i.e., under paced-mating conditions. Here, we demonstrate that sex-steroid priming required for female mating is anxiolytic; subsequent sexual activity under paced mating conditions did not disrupt this anxiolytic priming effect, whereas mating under unpaced conditions increased anxiety-related behavior. In primed females, the release of the neuropeptide oxytocin (OT) within the hypothalamic paraventricular nucleus was found to be elevated and to further increase during paced, but not unpaced mating. Central administration of an OT receptor antagonist partly prevented priming/mating-induced anxiolysis indicating the involvement of brain OT in the anxiolysis triggered by priming and/or sexual activity.These findings reveal that the positive consequences of mating in females are dependent on her ability to control sexual interactions, and that brain OT release is at least in part the underlying neurobiological correlate.

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