Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in the mesoaccumbens dopamine system.

The development of behavioral sensitization during repeated administration of psychomotor stimulants is a well characterized phenomenon which involves alterations in dopaminergic neurotransmission within the mesoaccumbens system. However, recent evidence indicating that both behavioral sensitization and certain of its neuronal correlates can be prevented by excitatory amino acid receptor antagonists suggests an integral role for glutamate systems in sensitization processes. Therefore, we have determined whether repeated psychomotor stimulant administration can alter responsiveness of the mesoaccumbens dopamine (DA) system to glutamate. After five daily injections of either cocaine (15.0 mg/kg) or d-amphetamine (5.0 mg/kg), rats were subjected to in vivo single cell recording to determine the efficacy of iontophoretically administered glutamate in altering the firing of ventral tegmental area DA neurons and nucleus accumbens neurons. Current-response determinations indicated that the responsiveness of ventral tegmental area DA neurons to glutamate was significantly enhanced in d-amphetamine-treated and cocaine-treated rats in that the neurons entered a state of apparent depolarization block at significantly lower iontophoretic currents. In contrast, nucleus accumbens neurons in psychomotor stimulant-treated rats were significantly less sensitive to the rate-enhancing effects of glutamate. Thus, sensitization appears to be associated with alterations in glutamate transmission at both the origin and termination of the mesoaccumbens DA pathway.