The purpose of this study was to determine whether neurons in the rostral ventrolateral medulla play a role in the sympathoinhibitory response elicited by i.v. administration of cocaine and, if so, to identify the type(s) of receptors involved. Adrenergic antagonists were microinjected bilaterally into the rostral ventrolateral medulla in pentobarbital-anesthetized rats in an attempt to block the decrease in sympathetic nerve discharge (SND) elicited by cocaine (1 mg/kg i.v.). After the bilateral microinjection of saline, cocaine elicited a -56 +/- 5% (mean +/- S.E.) decrease in SND lasting 36 +/- 3 min. Cocaine also increased arterial pressure (21 +/- 3 mm Hg). Prior microinjection of the alpha-2 adrenergic antagonist idazoxan (0.3, 3 or 10 nmol) did not alter the magnitude of the sympathoinhibitory response to cocaine; however, the duration of the response was significantly reduced by all 3 doses (range 21 +/- 3 to 11 +/- 2 min). Similarly, microinjection of the alpha-2 adrenergic antagonist piperoxan (10 nmol) decreased the duration (from 45 +/- 8 to 23 +/- 4 min), but not the magnitude of the sympathoinhibitory response. Microinjection of either the alpha-1 adrenergic antagonist terazosin (0.24 nmol) or the beta adrenergic receptor antagonist propranolol (2 nmol) did not attenuate the decrease in SND elicited by cocaine. The cocaine-mediated pressor response was not affected by any of the antagonist treatments. These data show that the decrease in SND elicited by cocaine is mediated centrally and involves, at least in part, the activation of alpha-2 adrenergic receptors in the rostral ventrolateral medulla.