Amphetamine-induced glutamate efflux in the rat ventral tegmental area is prevented by MK-801, SCH 23390, and ibotenic acid lesions of the prefrontalcortex

We showed previously that amphetamine challenge produces a delayed increase in glutamate efflux in the ventral tegmental area of both naive and chroni c amphetamine-treated rats. The present study examined the mechanisms under lying this response. The NMDA receptor antagonist MK-801 (0.1 mg/kg, i.p,) or the D1 dopamine receptor antagonist SCH 23390 (0.1 mg/kg, i.p,), given 3 0 min before acute amphetamine (5 mg/kg, i.p.), prevented amphetamine-induc ed glutamate efflux. Neither antagonist by itself altered glutamate efflux. Ibotenic acid lesions of the prefrontal cortex similarly prevented ampheta mine-induced glutamate efflux, while producing a trend toward decreased bas al glutamate levels (82.8% of sham group). Previous work has shown that the doses of NMDA and D1 receptor antagonists used in this study prevent the i nduction of behavioral sensitization when coadministered repeatedly with am phetamine, and that identical prefrontal cortex lesions performed before re peated amphetamine prevent the induction of ambulatory sensitization. Thus, treatments that prevent acute amphetamine from elevating glutamate efflux in the ventral tegmental area also prevent repeated amphetamine from elicit ing behavioral sensitization. These findings suggest that repeated elevatio n of glutamate levels during a chronic amphetamine regimen may contribute t o the cascade of neuroadaptations within the ventral tegmental area that en ables the induction of sensitization.