Excitation of nigral dopamine neurons by the GABA(A) receptor agonist muscimol is mediated via release of glutamate

Previous electrophysiological studies have shown that the GABA(A)receptor a gonist muscimol is able to markedly increase the firing rate of rat nigral dopamine (DA) neurons. This action of the drug is paradoxical since local m icroiontophoretic application of the drug is associated with a clearcut inh ibition of this neurons. In the present electrophysiological study, an atte mpt was made to analyze the mechanism of this action of the drug. Administr ation of muscimol (0.25-4.0 mg/kg, i.v.) was associated with a dose-depende nt increase in firing rate as well as an increased bursting activity of the nigral DA neurons. Both these effects of muscimol were clearly antagonised by intravenous administration of the NMDA receptor antagonist MK 801(1 mg/ kg) or by intracerebroventricular administration of the broadspectrum excit atory amino acid receptor antagonist kynurenic acid. Furthermore, pretreatm ent with PNU 156561A (40 mg/kg, i.v., 5-8h), a compound that raised endogen ous kynurenic acid levels about 9 times, also clearly antagonised the actio ns of muscimol. Indeed, this treatment reversed the excitatory action of mu scimol into an inhibitory effect on the nigral DA neurons. Here, we report that the excitatory action of muscimol is mediated indirectly by release of glutamate. (C) 2000 Elsevier Science Inc. All rights reserved.