Two subdivisions of the nucleus accumbens (NAC), the core and the shell, have been recently identified on the basis of immunohistochemical differences and neural connections. A major neural input to the NAC is provided by glutamatergic afferents of allocortical origin and there is evidence that glutamate can modulate psychomotor activation and drug reinforcement. This study was undertaken to explore whether selective pharmacological blockade of NMDA neurotransmission within the core and the shell region affected differentially spontaneous and cocaine-induced locomotor activity. We report that intra-NAC microinfusion of aminophosphonovaleric acid (AP-5) (0.75-3.0 micrograms/side, 1.5-6.0 micrograms total dose) within the core but not the shell region reduced cocaine-induced locomotion in a dose-dependent manner. In contrast, microinfusion of the same doses of AP-5 within the shell region caused a dose-dependent increase of spontaneous locomotion, while microinfusion within the core region was ineffective. These results indicate that blockade of NMDA receptors in the core and the shell of the NAC elicited different effects on spontaneous and cocaine-induced locomotion. This suggests that these substructures may subserve different functions within the integrated output of the NAC, functions that may vary according to the state of arousal.