Search

Noradrenergic afferents to hypothalamic corticotropin releasing hormone (CRH) neurons provide a major excitatory drive to the hypothalamic-pituitary-adrenal (HPA) axis via α1 adrenoreceptor activation. Noradrenergic afferents are recruited preferentially by somatic, rather than psychological, stress stimuli. Stress-induced glucocorticoids feed back onto the hypothalamus to negatively regulate the HPA axis, providing a critical autoregulatory constraint that prevents glucocorticoid overexposure and neuropathology. Whether negative feedback mechanisms target stress modality-specific HPA activation is not known. Here, we describe a desensitization of the α1 adrenoreceptor activation of the HPA axis following acute stress in male mice that is mediated by rapid glucocorticoid regulation of adrenoreceptor trafficking in CRH neurons. Glucocorticoid-induced α1 receptor trafficking desensitizes the HPA axis to a somatic but not a psychological stressor. Our findings demonstrate a rapid glucocorticoid suppression of adrenergic signaling in CRH neurons that is specific to somatic stress activation, and they reveal a rapid, stress modality-selective glucocorticoid negative feedback mechanism. [Display omitted] • Stress-induced glucocorticoid suppresses norepinephrine activation of CRH neurons • The rapid glucocorticoid effect is mediated by α1 adrenoreceptor desensitization • The glucocorticoid effect is specific to somatic, not psychological, stress • This reveals a stress modality-specific rapid glucocorticoid feedback mechanism Physical and psychological stressors activate neuroendocrine secretion of corticosteroid. Noradrenaline circuits are critical to the neuroendocrine response to physical but not psychological stress. Jiang et al. show that stress-induced corticosteroids decrease noradrenaline sensitivity in the brain, which suppresses the response to subsequent physical stressors but leaves the psychological stress response intact. [ABSTRACT FROM AUTHOR]

Abstract: Rhes is one of several signaling molecules preferentially expressed in the striatum. This GTP-binding protein affects dopamine-mediated signaling and behavior. Denervating the striatum of its dopaminergic inputs in adulthood reduces rhes mRNA expression. Here we show that dopamine depletion in adult rats by 6-hydroxydopamine caused a significant decrease in striatal Rhes protein levels as measured by Western blotting. The role of dopamine input on rhes mRNA induction during ontogeny was also examined. Rhes mRNA was measured on postnatal days 4, 6, 8, 10, 15, and 24 with in situ hybridization to determine its normal ontogeny. Signal in striatum was detectable, but very low, on postnatal day 4 and increased gradually to peak levels at days 15 and 24. Outside of the striatum, rhes mRNA was expressed at high levels in hippocampus and cerebellum during the postnatal period. Hippocampal signal was initially highest in CA3 and dentate gyrus, but shifted to higher expression in CA1 by the late postnatal period. Several other nuclei showed low levels of rhes mRNA during ontogeny. Depletion of dopamine by 6-hydroxydopamine injection on postnatal day 4 did not affect the ontogenetic development of rhes mRNA, such that expression did not differ statistically in lesioned versus vehicle-treated animals tested in adulthood. These findings suggest that although dopamine input is not necessary for the ontogenetic development of rhes mRNA expression, changes in both rhes mRNA and Rhes protein are integral components of the response of the adult striatum to dopamine depletion. [Copyright &y& Elsevier]

Abstract: Rhes, the Ras Homolog Enriched in Striatum, is an intermediate-size GTP binding protein. Although its full functions are not yet known, it has been shown to affect signaling and behaviors mediated by G protein-coupled receptors. Here we have tested whether Rhes affects behaviors mediated by opioid receptors. Wild type and rhes-deficient mice were administered morphine and tested for analgesia in formalin and tail flick tests. Rhes−/− mice showed significantly enhanced analgesia in both tests relative to rhes+/+ mice. Furthermore, rhes−/− mice did not display tolerance to repeated morphine administration and displayed significantly less withdrawal than rhes+/+ mice. These findings indicate that Rhes is involved in behaviors mediated by mu opioid receptors and in the adaptive response to repeated morphine administration. [ABSTRACT FROM AUTHOR]