Alterations in dopamine transmission in the nucleus accumbens, which is composed of two anatomically distinct compartments termed the shell and core, contribute to the expression of cocaine-induced behavioral sensitization. To test potential presynaptic components of behavioral sensitization, the behavioral and neurochemical response to amphetamine administration in the accumbens shell and core was measured at early (days 1-3) and late (days 20-22) withdrawal in rats pretreated with systemic cocaine (15 mg/kg x 2 days, 30 mg/kg x 5 days) or saline. Behavioral sensitization was observed at late, but not early withdrawal when amphetamine was microinjected into the nucleus accumbens shell of cocaine-pretreated rats. There were no significant differences between cocaine- and saline-pretreated animals when behavior was monitored after amphetamine injections into the core at either withdrawal period. After both withdrawal periods, the amphetamine-induced increase in extracellular dopamine was potentiated among cocaine-pretreated animals in the shell by the local administration of amphetamine (0.03, 0.3, 3.0 and 30 microM through the dialysis probe). In the core at early withdrawal there was tolerance to the amphetamine-induced increase in extracellular dopamine in the cocaine group, whereas there was no difference between the repeated saline and cocaine groups at late withdrawal. In a second experiment designed to evaluate potential postsynaptic influences, the D1 partial agonist, SFK-38393 (0.01 or 0.1 microgram/side), was microinjected into the nucleus accumbens core or shell regions after behavioral sensitization to cocaine. Although there was a motor-stimulant effect of SKF-38393 at both withdrawal periods, there was no difference between rats pretreated with repeated cocaine or saline. Collectively, these results demonstrate that the augmentation in dopamine transmission in the nucleus accumbens that is associated with behavioral sensitization is more robust in the shell than the core.