In previous studies we demonstrated that dopamine, specifically a D2-receptor system, in the frontal cortex of the mouse functions to inhibit the motor response elicited by systemically administered amphetamine or cocaine; the inhibition appears to be the result of the dopaminergic activation of a GABAergic system. In the present study the inhibitory role of dopamine and GABA in the cortex was investigated in animals that were behaviorally sensitized to stimulant-induced stereotypy. For these studies various dopaminergic and GABAergic drugs were injected intracortically (i.c.) and their effects on stimulant-induced stereotypy were compared in nonsensitized and sensitized mice. The results indicate that the dopaminergic system in the cortex of sensitized animals, in contrast to nonsensitized controls, no longer functions to inhibit the motor response to the stimulants. The change in dopaminergic function in sensitized animals appears to be the result of a qualitative change in the D2 dopamine receptor system and not the result of a change in the associated GABA system. The loss of the inhibitory activity of dopamine in the cortex correlated with the persistence of sensitization. These results suggest a new mechanism to account for behavioral sensitization; that is, the phenomenon is the result of a loss of stimulant-induced dopaminergic inhibition of motor activity normally mediated by the frontal cortex.