The administration of cocaine to rats causes the release of adrenocorticotropin hormone (ACTH). The observation that immunoneutralization of endogenous corticotropin-releasing factor (CRF) significantly blunts this response has suggested the importance of CRF-dependent pathways in this response. As the paraventricular nucleus (PVN) of the hypothalamus represents a major source of the CRF delivered to the pituitary, the present studies investigated the role of this hypothalamic nucleus in mediating cocaine-induced ACTH secretion. We first observed that one single iv injection of 5 mg cocaine/kg, or two sequential sc injections of 40 mg cocaine/kg, caused a measurable increase in steady-state levels of CRF mRNA. Bilateral lesions of the PVN significantly (P < 0.01) decreased the ability of cocaine to release ACTH measured 15 min later. Though we failed to measure any changes in the levels of the mRNA encoding for vasopressin (VP) following either regimen of drug administration, we noted that rats in which the magnocellular portion of the PVN (which contains VP perikarya) was spared, showed a normal ACTH response to cocaine. We therefore studied the possibility that VP might regulate the activity of the corticotrophs in response to cocaine. However, prior iv injection of polyclonal antibodies against VP did not measurably alter cocaine-induced ACTH secretion, while in the same experiment, immunoneutralization of endogenous CRF completely blocked the stimulatory action of cocaine. Taken together, these results show that CRF of PVN origin represents the major modulator of ACTH released in response to cocaine, while VP does not appear to play an important role.