REPEATED DAILY COCAINE ALTERS SUBSEQUENT COCAINE-INDUCED INCREASE OF EXTRACELLULAR DOPAMINE IN THE MEDIAL PREFRONTAL CORTEX

Male Sprague-Dawley rats that were naive or that had been treated with five daily saline or cocaine injections (15 mg/kg i.p.) were subseque ntly challenged with an injection of cocaine, and extracellular dopami ne content in the medial prefrontal cortex (mPFC) was measured using i n vivo microdialysis. Cocaine challenge increased extracellular dopami ne levels from base line in all three groups of rats, but the augmenta tion was significantly reduced in the cocaine-pretreated group, compar ed with the saline-pretreated group. In contrast, mPFC dopamine levels were not different among groups after challenge with systemic d-amphe tamine. To test whether repeated cocaine treatment led to altered rele asability of dopamine from mPFC terminals, challenge with KCI (10, 30 or 100 mM) or d-amphetamine (3, 30 or 300 mu M) was made via infusion through the dialysis probe into the mPFC. No differences in dopamine l evels were found between treatment groups for either drug at any dose. To determine whether the effects of cocaine were mediated by local ac tions within mPFC dopamine terminals, a cocaine challenge was administ ered through the microdialysis probe (1, 10 or 100 mu M). In contrast to the systemic cocaine challenge, local infusion of cocaine elicited a significant increase in daily cocaine-pretreated rats, compared with saline-pretreated controls, at the lowest dose tested, with no differ ences at the higher two doses. In summary, daily cocaine-pretreated ra ts demonstrated a suppressed mPFC dopamine response to subsequent syst emic, but not local, cocaine challenge. The results suggest that this apparent tolerance is not due to altered releasability of dopamine fro m mPFC terminals and may rely on altered afferent regulation of mesoco rtical dopamine neurons.