Calcitonin gene-related protein (CGRP) inhibits food intake and stimulates the hypothalamo-pituitary-adrenal (HPA) axis after intracerebroventricular injection in rats. However, the hypothalamic site and mechanism of action are unknown. We investigated the effects of intraparaventricular nucleus administration (iPVN) of CGRP on food intake and the HPA axis in rats and the effect of CGRP on the release of hypothalamic neuropeptides in vitro. In addition, we investigated the effects of food deprivation on hypothalamic CGRP expression. CGRP dose-dependently reduced food intake in the first hour after iPVN injection in fasted male rats (saline, 5.1 +/- 0.8 g; 0.3 nmol CGRP, 1.1 +/- 0.5 g; P < 0.001 vs. saline). iPVN injection of CGRP(8-37) (a CGRP(1) receptor antagonist) alone had no effect on food intake. However, the reduction in food intake by iPVN CGRP was attenuated by prior administration of CGRP(8-37) [CGRP(8-37) (10 nmol)/CGRP (0.3 nmol), 3.0 +/- 0.8 g; P < 0.05 vs. 0.3 nmol CGRP]. CGRP (100 nM) stimulated the release of alpha-melanocyte stimulating hormone, cocaine- and amphetamine-related transcript, corticotropin-releasing hormone, and arginine vasopressin from hypothalamic explants to 127 +/- 19%, 148 +/- 10%, 158 +/- 17%, and 198 +/- 21% of basal levels, respectively (P < 0.05 vs. basal), but did not alter the release of either neuropeptide Y or agouti-related protein. Hypothalamic CGRP mRNA levels in 24-h fasted rats were increased to 130 +/- 8% of control levels [CGRP mRNA (arbitrary units), 4.75 +/- 0.4; controls, 3.65 +/- 0.34; P < 0.05]. Our data suggest that CGRP administered to the PVN inhibits food intake and stimulates the HPA axis.