Amphetamine-induced plasticity of AMPA receptors in the ventral tegmental area: Effects on extracellular levels of dopamine and glutamate in freely moving rats

Previous electrophysiological studies suggested that the initiation of behavioral sensitization to cocaine and amphetamine involves a transient increase in AMPA receptor responsiveness in the ventral tegmental area (VTA). To test this, we used in vivo microdialysis to examine the effects of intra-VTA administration of AMPA (10 muM) and NMDA (100 muM) on dopamine (DA) and glutamate efflux in the VTA and the nucleus accumbens (NAC), an important target of VTA DA neurons. We compared rats treated for 5 d with saline or 5 mg/kg amphetamine and withdrawn for 3 or 10-14 d. After 3 d of withdrawal, intra-VTA AMPA increased both NAC and VTA DA levels to a greater extent in the amphetamine group, whereas NMDA produced similar effects in the saline and amphetamine groups. This enhanced responsiveness to AMPA was no longer evident in rats tested 10-14 d after the last injection. In addition, intra-VTA AMPA but not NMDA increased both VTA and NAC glutamate levels in rats tested 3 d after the last injection of amphetamine but not in saline controls. After 10-14 d, the responsiveness of glutamate levels to AMPA was no longer evident in the NAC but persisted in the VTA. Additional studies indicated that the glutamate effect in the NAC may involve increased responsiveness of DA receptors within the NAC. These findings establish an in vivo animal model with which to explore the consequences of repeated drug administration for AMPA receptor plasticity in the VTA. They also indicate that repeated amphetamine leads to potentiated interactions between DA and glutamate transmission.