Stress is a complex human experience having both positive and negative motivational properties. When chronic and uncontrollable, the adverse effects of stress on human health are considerable and yet poorly understood. Here, we report that the dysphoric properties of chronic stress are encoded by the endogenous opioid peptide dynorphin acting on specific stress-related neuronal circuits. Using different forms of stress presumed to evoke dysphoria in mice, we found that repeated forced swim and inescapable footshock both produced aversive behaviors that were blocked by a �-opioid receptor (KOR) antagonist and absent in mice lacking dynorphin. Injection of corticotropin-releasing factor (CRF) or urocortin III, key mediators of the stress response, produced place aversion that was also blocked by dynorphin gene deletion or KOR antagonism. CRF-induced place aversion was blocked by the CRF2 receptor antagonist antisauvigine-30, but not by the CRF1 receptor antagonist antalarmin. In contrast, place aversion induced by the KOR agonist U50,488 was not blocked by antisauvigine-30. These results suggest that the aversive effects of stress were mediated by CRF2 receptor stimulation of dynorphin release and subsequent KOR activation. Using a phospho-selective antibody directed against the activated KOR to image sites of dynorphin action in the brain, we found that stress and CRF each caused dynorphin-dependent KOR activation in the basolateral amygdala, nucleus accumbens, dorsal raphe, and hippocampus. The convergence of stress-induced aversive inputs on the dynorphin system was unexpected, implicates dynorphin as a key mediator of dysphoria, and emphasizes �-receptor antagonists as promising therapeutics. Key words: dynorphin; aversion; stress-induced aversion; drug addiction; �-opioid receptor; corticotropin releasing factor

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The distribution, pharmacology and function of the arginine vasopressin (Avp) 1b receptor subtype (Avpr1b) has proved more challenging to investigate compared to other members of the Avp receptor family. Avp is increasingly recognised as an important modulator of the hypothalamic–pituitary–adrenal (HPA) axis, an action mediated by the Avpr1b present on anterior pituitarycorticotrophs. The Avpr1b is also expressed in some peripheral tissues including pancreas and adrenal, and in the hippocampus (HIP), paraventricular nucleus and olfactory bulb of the rodent brain where its function is unknown. The central distribution of Avpr1bs is far more restricted than that of the Avpr1a, the main Avpreceptor subtype found in the brain. Whether Avpr1b expression in rodent tissues is dependent on differences in the length of microsatellite dinucleotide repeats present in the 5 0 promoter region of the Avpr1b gene remains to be determined. One difficulty of functional studies on the Avpr1b, especially its involvement in the HPAaxis response to stress, which prompted the generation of Avpr1b knockout (KO) mouse models, was the shortage of commercially available Avpr1b ligands, particularly antagonists. Research on mice lacking functional Avpr1bs has highlighted behavioural deficits in social memoryand aggression. The Avpr1b KO also appears to be an excellent model to study the contribution of the Avpr1b in the HPAaxis response to acute and perhaps some chronic (repeated) stressors where corticotrophin-releasing hormone and other genes involved in the HPA axis response to stress do not appear to compensate for the loss of the Avpr1b.

ABSTRACT We previously demonstrated colocalization of serotonin 1A (5- . This is the first in vivo demonstration of a prolonged heterologous intracellular desensitization of 5-HT 2A receptors after acute activation of 5-HT 1A receptors. These findings may provide insight into the long-term heterologous interactions between 5-HT 1A and 5-HT 2A receptor signaling that could occur in response to antidepressants, antipsychotics, or drugs of abuse that target these receptor subtypes. HT Serotonin (5-HT), a known stimulator of the hypothalamicpituitary-adrenal axis, plays an important role in mood disorders and impulse control (Carrasco and

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The effects of diazepam (0.2 mg/kg / during 21 days, i.p.) on behaviour, pituitary-adrenocortical and sympatho-adrenomedullary system of socially isolated and group-housed adult male rats additionally exposed to immobilization, were studied. Social isolation led to a shorter duration of grooming and longer latency to start grooming. Diazepam in social isolated rats reduced incorrect transitions percentage, but the number of grooming bouts, duration and latency to start grooming remained unchanged. Long-term isolation significantly elevated plasma ACTH and corticosterone, while not affecting noradrenaline and adrenaline. Diazepam decreased only plasma ACTH. Social isolation and immobilization significantly elevated all examined hormones. Immobilization of diazepam-treated isolated rats enhanced plasma ACTH, the increase being significantly lower, comparing to isolated vehicle-treated rats. Immobilization significantly increased plasma adrenaline, noradrenaline and corticosterone of diazepam- or vehicle-treated socially isolated rats. No differences in adrenaline, noradrenaline and corticosterone level between these two groups were observed. This indicates that chronic diazepam treatment of socially isolated rats changes some grooming behaviour parameters, but insignificantly affects stress-related adrenomedullary and adrenocortical alterations.

In social animals, hierarchical rank governs food availability, territorial rights and breeding access. Rank order can change rapidly and typically depends on dynamic aggressive interactions. Since the neuromodulator corticotrophin releasing factor (CRF) integrates internal and external cues to regulate the hypothalamic-pituitary adrenal (HPA) axis, we analyzed the CRF system during social encounters related to status. We used a particularly suitable animal model, African cichlid fish, Astatotilapia burtoni, whose social status regulates reproduction. When presented with an opportunity to rise in rank, subordinate A. burtoni males rapidly change coloration, behavior, and their physiology to support a new role as dominant, reproductively active fish. Although changes in gonadotropin-releasing hormone (GnRH1), the key reproductive molecular actor, have been analyzed during social ascent, little is known about the roles of CRF and the HPA axis during transitions. Experimentally enabling males to ascend in social rank, we measured changes in plasma cortisol and the CRF system in specific brain regions 15 minutes after onset of social ascent. Plasma cortisol levels in ascending fish were lower than subordinate conspecifics, but similar to levels in dominant animals. In the preoptic area (POA), where GnRH1 cells are located, and in the pituitary gland, CRF and CRF1 receptor mRNA levels are rapidly down regulated in ascending males compared to subordinates. In the Vc/Vl, a forebrain region where CRF cell bodies are located, mRNA coding for both CRFR1 and CRFR2 receptors is lower in ascending fish compared to stable subordinate conspecifics. The rapid time course of these

Elevated expression of c-fos in central nervous system correlates with visceral hypersensitivity in irritable bowel syndrome (IBS): a new target for IBS treatment

Stress activates the hypothalamo-pituitary-adrenal axis leading to enhanced glucocorticoid secretion and concurrently inhibits gonadotropin secretion and disrupts ovarian cyclicity. Here we tested the hypothesis that stress-like concentrations of cortisol interfere with follicular phase endocrine events of the ewe by suppressing pulsatile LH secretion, which is essential for subsequent steps in the preovulatory sequence. Cortisol was infused during the early to midfollicular phase, elevating plasma cortisol concentrations to one third, one half, or the maximal value induced by isolation, a commonly used model of psychosocial stress. All cortisol treatments compromised at least some aspect of reproductive hormone secretion in follicular phase ewes. First, cortisol significantly suppressed LH pulse frequency by as much as 35%, AVARIETY OF stressors inhibit gonadotropin secretion

We investigated whether inhalation of green odor (a mixture of equal amounts of trans-2-hexenal and cis-3-hexenol) prevents the skin-barrier disruption induced by chronic restraint stress in rats. To this end, transepidermal water loss (TEWL) was measured as an index of the disruption of skin-barrier function, whereas light- and electron-microscope examinations were performed to observe histological changes in the skin of the stressed animals. In addition, the effects on TEWL induced by chronic administration of a glucocorticoid, dexamethasone (DEX), were examined. Chronic restraint stress (8 h per day for 14 days) increased TEWL (vehicle + stress group). This effect (and the chronic stress–induced increase in adrenal weight) was prevented in rats that inhaled green odor at the beginning of each day’s restraint (2 h each day for 14 days; green odor + stress group). Electronmicroscope studies revealed that rats in the green odor + stress group possessed sufficient intercorneocyte lipids to create an effective skin barrier, although these had apparently been decreased in the vehicle + stress group. Daily administration of DEX for 14 days increased TEWL. The present results suggest that chronic stress–induced disruption of the skin barrier in rats can be reduced or prevented by green odor (possibly at least in part through an inhibitory effect on the stress-induced activation of the hypothalamo-pituitary-adrenocortical axis). Key words: adrenal gland, dexamethasone, hypothalamo-pituitary-adrenocortical axis, stratum corneum, transepidermal