The effects of i.v. cocaine self-administration under "naturalistic" conditions on plasma corticosterone (CORT) and prolactin (PRL) were investigated in male Sprague-Dawley rats. After the determination of plasma CORT and PRL levels under basal conditions before access to cocaine for self-administration, rats were allowed to self-administer cocaine (0.25, 0.5, 1.0, or 2.0 mg/kg/infusion i.v.) by pressing a response lever under a continuous schedule of cocaine reinforcement during five daily consecutive 10-h sessions. Plasma CORT was significantly increased and plasma PRL was significantly reduced after each of the five self-administration sessions. The effects of cocaine on plasma CORT were intake-dependent, as demonstrated by significant positive correlations between postsession plasma CORT and total cocaine intake within the preceding sessions. The effects of cocaine on PRL were also intake-dependent but only on the first day of self-administration, on which a significant negative correlation was observed between cocaine intake and postsession PRL. In contrast, significant correlations between PRL and cocaine intake were not observed during any subsequent session, apparently reflecting adaptations to cocaine-induced PRL release. Alterations in neuroendocrine homeostasis emerged over time. Reductions in presession CORT values, as well as a persistent blunting of the diurnal CORT peak, were observed. Similarly, there was a modest but significant attenuation of plasma PRL when measured 4 days after the termination of cocaine self-administration. Alterations in neuroendocrine function associated with self-administration may be related to the development of cocaine dependence and could contribute to relapse in abstinent users.