THE ROLE OF DOPAMINE IN THE MOUSE FRONTAL-CORTEX - A NEW HYPOTHESIS OF BEHAVIORAL SENSITIZATION TO AMPHETAMINE AND COCAINE

In previous studies we demonstrated that dopamine, specifically a D-2- receptor system, in the frontal cortex of the mouse functions to inhib it the motor response elicited by systemically administered amphetamin e or cocaine; the inhibition appears to be the result of the dopaminer gic activation of a GABAergic system. In the present study the inhibit ory role of dopamine and GABA in the cortex was investigated in animal s that were behaviorally sensitized to stimulant-induced stereotypy. F or these studies various dopaminergic and GABAergic drugs were injecte d intracortically (IC) and their effects on stimulant-induced stereoty py were compared in nonsensitized and sensitized mice. The results ind icate that the dopaminergic system in the cortex of sensitized animals , in contrast to nonsensitized controls, no longer functions to inhibi t the motor response to the stimulants. The change in dopaminergic fun ction in sensitized animals appears to be the result of a qualitative change in the D-2 dopamine receptor system and not the result of a cha nge in the associated GABA system. The loss of the inhibitory activity of dopamine in the cortex correlated with the persistence of sensitiz ation. These results suggest a new mechanism to account for behavioral sensitization; that is, the phenomenon is the result of a loss of sti mulant-induced dopaminergic inhibition of motor activity normally medi ated by the frontal cortex. (C) 1998 Elsevier Science Inc.