Dopamine-glutamate Interactions Research Articles

Elevated NMDA receptors in parkinsonian striatum.

Dopamine-glutamate interactions contribute to normal striatal function and have been implicated in neurotoxicity at nigrostriatal dopamine (DA) terminals. The present study examined the striata of idiopathic Parkinson's disease (PD) patients and age-matched controls for regional differences in the DA transporter and binding to N-methyl-D-aspartate (NMDA) receptors. [3H]Mazindol labeling of the DA transporter was reduced by 70-80% in the caudate and putamen of PD patients, with reductions being more extensive dorsally than ventrally. In contrast, L-[3H]glutamate binding to NDMA-sensitive receptors was 20-40% higher in PD cases than in controls. These findings raise the possibility that modifications occur within corticostriatal glutamate synapses of PD patients, possibly as a consequence of reduced nigrostriatal DA activity.

Striatal protection induced by lesioning the substantia nigra of rats subjected to focal ischemia.

Unilateral 6-hydroxydopamine lesion of the substantia nigra reduced the volume of striatal necrosis and suppressed the increase in extracellular glutamate concentration in the striatum induced by middle cerebral artery occlusion in rats. These results indicate that the dopaminergic nigrostriatal pathway is highly involved in the vulnerability of the striatum to ischemia and suggest that glutamate-dopamine interactions may play a key role in the striatal ischemic insult.

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 μg bilaterally) was microinjected immediately prior to amphetamine (5 μg 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.