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 beha vioral sensitization to cocaine and amphetamine involves a transient increa se in AMPA receptor responsiveness in the ventral tegmental area (VTA). To test this, we used in vivo microdialysis to examine the effects of intra-VT A administration of AMPA (10 muM) and NMDA (100 muM) on dopamine (DA) and g lutamate efflux in the VTA and the nucleus accumbens (NAC), an important ta rget of VTA DA neurons. We compared rats treated for 5 d with saline or 5 m g/kg amphetamine and withdrawn for 3 or 10-14 d. After 3 d of withdrawal, i ntra-VTA AMPA increased both NAC and VTA DA levels to a greater extent in t he amphetamine group, whereas NMDA produced similar effects in the saline a nd amphetamine groups. This enhanced responsiveness to AMPA was no longer e vident 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 t ested 3 d after the last injection of amphetamine but not in saline control s. After 10-14 d, the responsiveness of glutamate levels to AMPA was no lon ger evident in the NAC but persisted in the VTA. Additional studies indicat ed that the glutamate effect in the NAC may involve increased responsivenes s of DA receptors within the NAC. These findings establish an in vivo anima l model with which to explore the consequences of repeated drug administrat ion for AMPA receptor plasticity in the VTA. They also indicate that repeat ed amphetamine leads to potentiated interactions between DA and glutamate t ransmission.