Central vasopressin V1A receptor blockade alters patterns of cellular activation and prevents glucocorticoid habituation to repeated restraint stress exposure.

Our previous experiments implicated a role for the arginine vasopressin (AVP) V1A receptor subtype in mediating the normal decline (habituation) of hypothalamic-pituitary-adrenal (HPA) axis responses to repeated restraint exposure. To explore pathways mediating the endogenous effects of central AVP on stress HPA axis habituation, here we compared cellular (Fos) and hormone responses in male rats receiving chronic icv infusion of vehicle or a V1A receptor antagonist that began 7 d before stress testing, continued through the duration of acute and repeat restraint exposure. As a group, rats with V1A antagonism displayed a modest reduction in ACTH habituation, whereas the decline in corticosterone was completely prevented. V1A antagonized rats also showed reduced evidence of habituated Fos responses in the paraventricular nucleus of the hypothalamus, medial amygdala, and within the anterior division of the bed nucleus of the stria terminalis. Based on these cellular and neuroendocrine responses, we then examined whether repeated restraint is reflected by changes in V1A receptor binding. Relative to stress naïve animals, repeatedly exposed rats showed lower levels of V1A binding in the dentate gyrus of the hippocampus, thalamus and central amygdala, but higher levels in the septum and anterior BST. Taken together, these findings suggest that AVP may act within multiple targets to regulate the normal decline in stress-induced drive to the HPA axis, and that this may involve the net of V1A receptor stimulatory and inhibitory influences on neuroendocrine habituation.