Modulation of the mesolimbic dopamine system by glutamate: Role of NMDA receptors

Glutamate has been shown to modulate motor behavior, probably via N-methyl- D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that are involved in the control of the mesolimbic do pamine (DA) system, that is, the ventral tegmental area (VTA)-nucleus accum bens (NAC), In the present study, we investigated the effects of uncompetit ive (MK-801) and competitive [DL-2-amino-5-phosphonopentanoic acid (AP-5), CGP 40116] NMDA receptor antagonists and NMDA and AMPA on DA release in the mesolimbic system and on motor behavior. Systemic injection and intrategme ntal infusion of MK-801 increased DA levels in the VTA, but the systemic ad ministration enhanced DA exclusively in the NAC and increased motor behavio r. In contrast, intrategmental infusion of AP-5, but not the systemic admin istration of its lipophilic analogue CGP 40116, decreased the DA release in the two regions without affecting motor behavior. NMDA and AMPA infusion i nto the VTA increased DA levels in both areas. This increase was accompanie d by a strong motor behavioral stimulation after NMDA but only a moderate i ncrease after AMPA infusion, The present results indicate that mesolimbic D A neurons are controlled by the glutamatergic system and that the effects o f uncompetitive and competitive NMDA receptor antagonists on DA release are mediated by an interaction with different brain areas. These findings may account for the different effects of NMDA receptor ligands on motor behavio r.