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Social stress has deteriorating effects on various psychiatric diseases. In animal models, exposure to socially dominant conspecifics (i.e., social defeat stress) evokes a species-specific defeat posture via unknown mechanisms. Oxytocin neurons have been shown to be activated by stressful stimuli and to have prosocial and anxiolytic actions. The roles of oxytocin during social defeat stress remain unclear. Expression of c-Fos, a marker of neuronal activation, in oxytocin neurons and in oxytocin receptor‒expressing neurons was investigated in mice. The projection of oxytocin neurons was examined with an anterograde viral tracer, which induces selective expression of membrane-targeted palmitoylated green fluorescent protein in oxytocin neurons. Defensive behaviors during double exposure to social defeat stress in oxytocin receptor‒deficient mice were analyzed. After social defeat stress, expression of c-Fos protein was increased in oxytocin neurons of the bed nucleus of the stria terminalis, supraoptic nucleus, and paraventricular hypothalamic nucleus. Expression of c-Fos protein was also increased in oxytocin receptor‒expressing neurons of brain regions, including the ventrolateral part of the ventromedial hypothalamus and ventrolateral periaqueductal gray. Projecting fibers from paraventricular hypothalamic oxytocin neurons were found in the ventrolateral part of the ventromedial hypothalamus and in the ventrolateral periaqueductal gray. Oxytocin receptor‒deficient mice showed reduced defeat posture during the second social defeat stress. These findings suggest that social defeat stress activates oxytocin-oxytocin receptor systems, and the findings are consistent with the view that activation of the oxytocin receptor in brain regions, including the ventrolateral part of the ventromedial hypothalamus and the ventrolateral periaqueductal gray, facilitates social defeat posture.

The oxytocin receptor has been suggested to be involved in energy metabolism, such as food intake and energy consumption. Here, we demonstrate that oxytocin receptor-deficient (Oxtr−−) male mice exhibited late-onset obesity with increases in abdominal fat pads and fasting plasma triglycerides. Daily food intake and spontaneous motor activity of Oxtr−−mice were not significantly different as compared with wild-type mice. In contrast, brown adipose tissue in Oxtr−−mice contained large lipid droplets and cold-induced thermogenesis was impaired. This study demonstrates that oxytocin receptor plays essential roles in the regulation of energy homeostasis.

Cyclosporine induces psychological side effects but its mechanisms of action remain to be elucidated.

We examined the effects of i.c.v. administration of neuro-peptide W-30 (NPW30) on plasma arginine vasopressin (AVP) and plasma oxytocin (OXT) using RIA. The induction of c-fosmRNA, AVP heteronuclear (hn)RNA, and c-Fos protein (Fos) in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of rats were also investigated using in situhybridization histochemistry for c-fosmRNA and AVP hnRNA, and immunohistochemistry for Fos. Both plasma AVP and OXT were significantly increased at 5 and 15 min after i.c.v. administration of NPW30 (2.8 nmol/rat). In situhybridization histochemistry revealed that the induction of c-fosmRNA and AVP hnRNA in the SON and PVN were significantly increased 15, 30, and 60 min after i.c.v. administration of NPW30 (1.4 nmol/rat). Dual immunostaining for Fos/AVP and Fos/OXT revealed that both AVP-like immunoreactive (LI) cells and OXT-LI cells exhibited nuclear Fos-LI in the SON and PVN, 90 min after i.c.v. administration of NPW30 (2.8 nmol/rat). These results suggest that central NPW30 may be involved in the regulation of secretion of AVP and OXT in the magnocellular neurosecretory cells in the SON and PVN.

Objective: The Na,K‐ATPase α2 subunit gene (Atp1a2) is expressed in the brain, skeletal muscles, heart, and adipocytes. Specific function of the α2 subunit, such as involvement in differentiation and function of adipocytes, has not been addressed. The aim of this study was to examine whether Atp1a2‐defective heterozygous mice show obesity and reveal the mechanisms underlying the obesity. Research Methods and Procedures: We measured the differentiation and glucose uptake function of in vitro‐differentiated adipocytes derived from embryonic fibroblasts of Atp1a2‐defective mice. Food intake, body temperature, metabolic rate, and spontaneous activity and mRNA levels of neuropeptide genes were compared between the heterozygous and wild‐type adult mice. Results: Atp1a2heterozygous female mice developed obesity after middle age. The time course of in vitro adipocyte differentiation of embryonic fibroblasts isolated from wild type, heterozygous, and homozygous mice was not different, glucose and Rb uptake activities of the in vitro‐differentiated adipocytes were not altered, and the effects of insulin on glucose uptake and those of monensin and ouabain on Rb uptake were similar among the genotypes. However, food intake in the light phase was significantly greater in the heterozygous mice than the wild type in the 24‐hour dark‐light cycle, whereas it was similar under constant‐light condition. Body temperature, metabolic rate at rest, and spontaneous motor activity of the heterozygous mice were similar to those of the wild type. Orexin mRNA level was lower in heterozygous than wild‐type mice. Discussion: The Na,K‐ATPase α2 subunit is not involved in the differentiation or in glucose and Rb uptake function of in vitro‐differentiated adipocytes. Hyperphagia is the likely primary cause of obesity in Atp1a2heterozygous mice.

Galanin-like peptide is a recently identified neuropeptide. We examined the effects of stressful stimuli on expression of c-Fos protein in galanin-like peptide neurons, and the effects of central infusion of galanin-like peptide on release of stress hormones, vasopressin, oxytocin and adrenocorticotropic hormone, in male rats. Foot shock stress induced expression of c-Fos protein in galanin-like peptide neurons in the hypothalamus. Intracerebroventricular injection of galanin-like peptide significantly increased plasma concentrations of vasopressin, oxytocin and adrenocorticotropic hormone. Galanin-like peptide also increased blood pressure, heart rates and plasma glucose concentrations, but significantly changed neither plasma osmolality nor blood haemoglobin concentration. A neuropeptide Y-Y1 receptor antagonist, BIBP3226, did not significantly change galanin-like peptide-induced hormone release. It is possible that galanin-like peptide is involved in vasopressin, oxytocin and adrenocorticotropic hormone release from the pituitary during stress.

Various stressors are known to cause eating disorders. However, it is not known in detail about the neural network and molecular mechanism that are involved in the stress-induced changes of feeding behavior in the central nervous system. Many novel feeding-regulated peptides such as orexins/hypocretins and ghrelin have been discovered since the discovery of leptin derived from adipocytes as a product of the ob gene. These novel peptides were identified as endogenous ligands of orphan G protein–coupled receptors. The accumulating evidence reveals that these peptides may be involved in stress responses via the central nervous system, as well as feeding behavior. The possible lnvolvement of novel feeding-related peptides in neuroendocrine responses to stress is reviewed here.

Neuromedin U activates noradrenergic neurones in the medulla oblongata and oxytocin neurones in the hypothalamus. Here we examined roles of noradrenergic transmission in oxytocin release from the pituitary after intracerebroventricular administration of neuromedin U in rats. Neuromedin U administration facilitated noradrenaline release in the supraoptic nucleus. Administration of a 1 adrenoceptor antagonist, metoprolol, or a 2 antagonist, ICI 118551 but not an 1 antagonist, benoxathian, reduced increases in plasma oxytocin concentrations observed after administration of neuromedin U, but plasma ACTH concentrations were not significantly changed. All theses data suggest that neuromedin U stimulates oxytocin release from the pituitary, at least in part, via activation of adrenoceptors.

Noxious stimuli facilitate oxytocin release from the pituitary. Oxytocin cells receive excitatory synaptic inputs from the noradrenergic neurones located in the medulla oblongata. Oxytocin release after noxious stimuli is blocked by noradrenaline depletion in the brain. Here, we examined effects of noxious stimuli upon noradrenaline release within the supraoptic nucleus. Electric footshocks or mustard oil application to the foot pad facilitated noradrenaline release in the nucleus. Noradrenaline release after noxious stimuli was impaired by microinjections with a GABAAreceptor agonist, muscimol, or an α2 adrenoceptor agonist, clonidine, into the A1 noradrenergic cell regions. From these and reported data, we conclude that the medullary A1 noradrenergic neurones contribute, at least in part, to oxytocin release from the pituitary after noxious stimuli.

Oxytocin release from the neurohypophysis is facilitated by systemic cholecystokinin octapeptide (CCK) administration and noxious stimuli. Oxytocin release after CCK administration is mediated by A2 noradrenergic neurones while the release after noxious stimuli appears to be mediated by A1 noradrenergic neurones. On the other hand, facilitation of vasopressin release after noxious stimuli is not dependent upon noradrenergic neurones but on dopamine receptors. Environmental stimuli previously paired with noxious stimuli (conditioned fear stimuli) or novel environmental stimuli facilitate oxytocin release and suppress vasopressin release. These neuroendocrine responses to conditioned fear stimuli, but not to novel stimuli, are impaired by central noradrenaline depletion or i.c.v. adrenoceptor antagonists. These data suggest that there are at least two types of stress responses in neuroendocrine systems, one noradrenaline dependent, and one noradrenaline independent. It is also suggested that noradrenergic neurones are functionally heterogeneous in the control of oxytocin release.

The pineal gland secretes melatonin under an influence of suprachiasmatic nucleus neurones. Pinealectomy or melatonin administration affects behavioural responses to novel stimuli. Fear or novel stimuli inhibit vasopressin (VP) and facilitate oxytocin (OT) or prolactin (PRL) release from the pituitary. Thus the suprachiasmatic nucleus–pineal gland system may modulate VP, OT and PRL responses to conditioned fear stimuli. In the present experiments with male rats, pinealectomy or melatonin administration did not significantly change VP, OT or PRL responses to conditioned fear stimuli. Electrolytic lesions of the suprachiasmatic nuclei impaired VP but not OT or PRL responses. The results show that the pineal gland is not involved in neuroendocrine responses to conditioned fear stimuli and suggest that the suprachiasmatic nucleus is necessary for the VP response to fear stimuli.

In rats, noxious stimuli increase food intake while conditioned fear stimuli decrease it. Orexin neurones play a facilitative role in food intake. Here, we examined expression of Fos protein in orexin neurones after noxious or conditioned fear stimuli in rats. Noxious stimuli significantly induced Fos protein in orexin neurones. On the other hand, conditioned fear stimuli did not significantly change expression of Fos protein in orexin neurones. The results demonstrate selective activation of orexin neurones by noxious stimuli, suggesting that effects of stressful stimuli upon orexin neurones are dependent upon the stimuli used. This finding is consistent with an idea that orexin neurones are involved in stress-induced food intake.

Vasopressin is released not only from axon terminals in the neurohypophysis but also from soma/dendrite regions in the supraoptic nucleus. In order to investigate presynaptic roles of dendritically released vasopressin, we examined effects of local application of vasopressin upon noradrenaline release within the supraoptic nucleus by a microdialysis method. Noradrenaline release within the supraoptic nucleus was facilitated by local perfusion with high Kor an NMDA receptor antagonist. Vasopressin augmented noradrenaline increase after high Kbut reduced it after an NMDA receptor antagonist, AP-5. The results suggest that dendritically released vasopressin modulates noradrenaline release within the supraoptic nucleus in a bimodal fashion.

Nicotine injected in the supraoptic nucleus facilitates vasopressin release from the neurohypophysis. Nicotinic acetylcholine receptors have been found not only on vasopressin-producing cell bodies but also on presynaptic nerve terminals in the nucleus. Vasopressin cells receive excitatory synaptic inputs from noradrenergic neurones. To test whether nicotine facilitates noradrenaline release in the supraoptic nucleus, we perfused the supraoptic nucleus with nicotine through a microdialysis probe. Nicotine increased the extracellular noradrenaline concentrations in the nucleus. A noradrenaline uptake inhibitor, desipramine, increased the extracellular noradrenaline concentrations in the nucleus and did not block the noradrenaline increase after nicotine. The results suggest that nicotine acts within the supraoptic nucleus to facilitate noradrenaline release pre-synaptically. This presynaptic action may contribute, in part, to vasopressin release after nicotine.

Conditioned fear stimuli suppress motor activity. The fear stimuli suppress vasopressin and facilitate oxytocin and prolactin release. These fear responses are impaired by selective destruction of noradrenergic neurones. Adenosine 5′-triphosphate is co-released from noradrenergic nerve terminals with noradrenaline. Thus the possibility arises that the behavioural and neuroendocrine responses may be mediated by purinergic rather than noradrenergic synapses. We examined whether suramin, an inhibitor of P2 and NMDA receptors, blocks conditioned fear responses. Suramin injected i.c.v. 30 min before testing stimuli impaired conditioned fear responses. The role of purinergic P2 receptors in expression of the behavioural and neuroendocrine responses to conditioned fear stimuli is discussed.