Nicotine stimulates the secretion of catecholamines from sympathetic nerve endings and adrenal medulla by acting on peripheral nicotinic cholinergic receptors. Nicotine is also a potent stimulant in the central nervous system but the significance of nicotinic receptors in brain in mediating cardiovascular and sympathoadrenal responses to nicotine is unclear. The responses of resting plasma catecholamines, blood pressure and heart rate were compared in rats receiving nicotine, administered either systemically or intracerebroventricularly (i.c.v.). Sympathoadrenal stress responses were also studied in rats rendered tolerant to nicotine from repeated systemic or intraventricular injections. Nicotine, given either intraventricularly or systemically, produced dose-related increases in the concentration of epinephrine in plasma. Little effect on norepinephrine in plasma was observed with nicotine given intraventricularly, indicating predominant stimulation of adrenomedullary pathways. In contrast, nicotine, given systemically, produced comparable increases in both epinephrine and norepinephrine. Blood pressure increased and heart rate fell in response to either intraventricular or systemic administration of nicotine. Rats exhibited tolerance to nicotine 24 hr after a single intraventricular injection; however, tolerance was not detected with systemically injected nicotine unless the injections were given at least every 30 min. Whereas rats rendered tolerant to systemic administration of nicotine were cross-tolerant to stress, with respect to sympathoadrenal stimulation, cross-tolerance with stress was not detected in rats treated with nicotine repeatedly by the intraventricular route. These results indicate that nicotinic receptors in brain modulate the central sympathetic outflow and adapt readily to nicotine stimulation with prolonged tolerance, but are probably not involved in sympathoadrenal stress responses. Peripheral nicotinic receptors, regulating sympathoadrenal secretion of catecholamines, displayed much shorter-lasting tolerance.