The effects of acute and repeated daily cocaine on the levels of mRNA coding for glutamic acid decarboxylase (GAD), preproenkephalin (PPE), preprotachykinin (PPT), and the dopamine D2 receptor were determined in the striatum, nucleus accumbens core and shell areas (NAcore, NAshell), and medial prefrontal cortex. Rats were given repeated saline or cocaine for 6 days. A cocaine challenge administered 24 h later resulted in an augmented locomotor response in daily cocaine-pretreated rats. Six h after the challenge, rats were sacrificed and Northern blot analysis revealed that acute cocaine increased GAD mRNA levels by 44% in the NAshell, while repeated cocaine prevented the acute cocaine-induced increase. These data suggest that cocaine may differentially regulate GABA release at NA core and shell projection fields.