The central mechanism(s) whereby peripherally administered nicotine (N) stimulates prolactin secretion has not been clarified. The current studies showed that an i.c.v. injection of N into the fourth ventricle (IV) produced a significant dose-dependent elevation of plasma prolactin [buffer less than N 0.125 micrograms = N 0.25 micrograms (P less than .05) less than N 0.5 micrograms = N 2.5 micrograms (P less than .01)]. Injecting the nicotinic cholinergic (NAch) antagonist, mecamylamine, into the IV (20 or 40 micrograms) or i.v. (0.5 mg/kg b.wt.) before the administration of N by the alternate route indicated that nicotine was activating NAch receptors accessible from the IV. Because brain stem catecholaminergic cell groups, adjacent to the IV, project to hypothalamic regions involved in modulating prolactin release, the involvement of IV catecholaminergic neurons in N-stimulated prolactin release was investigated. Ablation of central catecholaminergic neurons by 6-hydroxydopamine abolished the prolactin response to N injected i.c.v. (1 or 2.5 micrograms; P less than .05) or i.v. (0.03 or 0.05 mg/kg b.wt.; P less than .05). To assess the role of norepinephrine and epinephrine, LY 10853, an inhibitor of dopamine-beta-hydroxylase, was given i.p. 4 h before i.v. nicotine; the prolactin response was attenuated (P less than .01). Selective inhibitors of epinephrine synthesis, SKF 64139 or 2,3-dichloro-alpha-methylbenzylamine, administered on the same schedule, reduced (P less than .01) the prolactin response to N without altering responsiveness to the dopamine receptor antagonist, domperidone.(ABSTRACT TRUNCATED AT 250 WORDS)