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 agonist muscimol is able to markedly increase the firing rate of rat nigral dopamine (DA) neurons. This action of the drug is paradoxical since local microiontophoretic application of the drug is associated with a clearcut inhibition of this neurons. In the present electrophysiological study, an attempt was made to analyze the mechanism of this action of the drug. Administration of muscimol (0.25-4.0 mg/kg, i.v.) was associated with a dose-dependent 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 broad-spectrum excitatory amino acid receptor antagonist kynurenic acid. Furthermore, pretreatment with PNU 156561A (40 mg/kg, i.v., 5-8h), a compound that raised endogenous kynurenic acid levels about 9 times, also clearly antagonised the actions of muscimol. Indeed, this treatment reversed the excitatory action of muscimol 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.
Erhardt
S
S
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden. sophie.erhardt@fyfa.ki.se
Engberg
G
G
D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D018698:Glutamic Acid / Q000378:metabolism*; D007736:Kynurenic Acid / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009118:Muscimol / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*
D002087:Butyrates; C104254:FCE 28833; D018755:GABA Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D009118:Muscimol; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D007736:Kynurenic Acid; D004298:Dopamine