PACAP regulates neuroendocrine and behavioral stress responses via CRF-containing neurons of the rat hypothalamic paraventricular nucleus

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide widely distributed in the brain including the hypothalamic paraventricular nucleus (PVN) implying a regulatory role in stress function. Recent evidence indicates that one of the main targets of PACAP within the PVN are corticotropin-releasing factor (CRF) neurons, which are key regulators of the hypothalamic-pituitary-adrenal (HPA) axis. However, the neural correlates that mediate PACAP effects on stress function are not fully understood. In the present study, we characterized the neuronal mechanism by which PACAP regulates neuroendocrine and behavioral stress responses in rats. We found that intracerebroventricular administration of PACAP increased the swim stress-induced c-Fos expression in distinct brain areas of the stress and anxiety circuitry including the parvocellular part of the PVN and changed behavioral stress coping during forced swimming to a more passive coping style (i.e., indicated by increased floating and reduced struggling behavior). Subsequently, PACAP administration directly into the PVN mimicked these behavioral effects and potentiated the plasma ACTH response to forced swim stress suggesting an excitatory role of PACAP on HPA stress axis reactivity. In addition, immunohistochemical analysis revealed a considerable portion of stress-activated CRF neurons in the medial parvocellular part of the PVN that co-localized PAC1 receptors suggesting that PACAP-induced effects on stress function are likely mediated directly by activation of CRF neurons in the PVN. Thus, these findings suggest that the PVN may represent one of the key areas where PACAP regulates the neuroendocrine and behavioral stress response.