NMDA receptors mediate the behavioral effects of amphetamine infused into the nucleus accumbens.

The present experiments examined glutamate-dopamine interactions within the nucleus accumbens in rats. It has been hypothesized that dopaminergic nerve terminals exert a modulatory influence on glutamate-mediated signals from corticolimbic areas. In the present studies, the effect of the selective NMDA (n-methyl-d-aspartate) antagonist AP5 (2-amino-5-phosphonopentanoic acid) on amphetamine-mediated behaviors was observed. In two behavioral paradigms, AP5 (0, 0.05, 0.5, 1.0 micrograms bilaterally) was microinjected immediately prior to amphetamine (5 micrograms bilaterally) in the nucleus accumbens. In the first experiment, the influence of AP5 on amphetamine-induced motor activity was examined. AP5 dose-dependently reduced the effectiveness of amphetamine in stimulating motor behavior. AP5 alone, paradoxically, tended to increase motor activity. In the second experiment, the effects of AP5 on amphetamine-potentiated responding (lever pressing) for conditioned reward (CR) were investigated. Normally, when amphetamine is infused into the nucleus accumbens, a marked potentiation of CR responding occurs. Prior infusion of AP5 also attenuated this behavioral effect of amphetamine. The results demonstrate that NMDA receptors within the nucleus accumbens mediate the behavioral consequences of increased dopamine release. They provide additional evidence for the involvement of limbic-striatal connections in the activating and reinforcing effects of psychostimulant drugs.