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.