Amphetamine and D1 Dopamine Receptor Agonists Produce Biphasic Effects on Glutamate Efflux in Rat Ventral Tegmental Area: Modification by Repeated Amphetamine Administration

Amphetamine or selective D1 and D2 dopamine receptor agonists and antagonists were administered to the ventral tegmental area (VTA) through a microdialysis probe to determine their effects on glutamate and aspartate efflux in rats pretreated for 5 days with vehicle or 5 mg/kg (+)‐amphetamine sulfate. In vehicle rats, glutamate efflux declined during 2 h of perfusion with the D1 receptor agonist SKF‐82958 (10 and 100 µ M ). After SKF‐82958 perfusion ended, glutamate efflux rebounded to basal levels and continued to increase gradually over the next 2 h. A similar biphasic pattern was observed with intra‐VTA amphetamine (10 and 100 µ M ) and with another D1 agonist (100 µ M SKF‐38393). The biphasic effects of SKF‐82958 were prevented by coperfusion with a D1 antagonist (SCH‐23390; 30 µ M ). Glutamate efflux was unaffected by a D2 agonist (100 µ M quinpirole) and by D1 or D2 antagonists administered alone (SCH 23390 and eticlopride; 30 µ M ). In amphetamine‐pretreated rats tested 2 days after the last injection, both the decrease during SKF‐82958 perfusion and the delayed increase in glutamate efflux were attenuated. In rats tested 12–14 days after the last amphetamine injection, only the decrease during SKF‐82958 perfusion was attenuated. None of these drug treatments produced consistent effects on aspartate efflux. We showed previously that systemic amphetamine (5 mg/kg, i.p.) has no immediate effect on VTA glutamate efflux but produces a delayed increase in glutamate efflux that reaches statistical significance 2–3 h after injection. Because behavioral sensitization can be elicited either by repeated systemic or repeated intra‐VTA administration, neurochemical effects common to both routes (such as the delayed increase in glutamate efflux) are most likely to contribute to its induction.