Cocaine (COC) has been described as exerting potent stimulatory effects on the hypothalamo-pituitary-adrenocortical (HPA) axis. In the present study, we investigated the acute and chronic effects of intracerebroventricular and intrahypothalamic injections of COC in rats. Twenty minutes following intracerebroventricular injection of COC (1-100 micrograms), dose-dependent increases in plasma corticosterone (CS) were observed, although the highest dose tested (100 micrograms) evoked a significantly smaller response than that following 50 micrograms. Prior stressing of the animals resulted in elevated plasma CS levels (315 +/- 16 ng/ml) and significantly decreased plasma CS concentrations following 50 micrograms COC (87.8 +/- 3.2%). Injections above the hypothalamic paraventricular nucleus (PVN), the site of corticotropin-releasing-factor-secreting neurons which regulate HPA activity, required relatively higher doses of COC in order to elicit increases in plasma CS; injections of 0.5 microgram had no effect, 1 microgram resulted in an increase to 168 +/- 68 ng/ml (p < 0.005), and 2.5 micrograms produced an increase to 146 +/- 29 ng/ml (p < 0.025). Post-PVN injections of COC, behind the posterior margin of the PVN in the vicinity of the ventral noradrenergic ascending bundle, also required a high dose (2.5 micrograms) in order to elicit a plasma CS response (208 +/- 19 ng/ml; p < 0.005), with no significant response seen following 0.5 microgram COC. No effects of specific neurotoxic lesions of the catecholaminergic or serotonergic innervation of the hypothalamus were observed upon adrenocortical responses to COC.(ABSTRACT TRUNCATED AT 250 WORDS)