Prototypic GABAA receptor agonist muscimol acts preferentially through forebrain high-affinity binding sites

Dev Chandra, Lauri M. Halonen, Anni Maija Linden, Chiara Procaccini, Kati Hellsten, Gregg E. Homanics, Esa R. Korpi

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Muscimol has been regarded as a universal agonist for all γ-aminobutyric acid type A receptor (GABAA-R) subtypes. However, brain regional distribution of muscimol's high-affinity binding sites greatly differs from those of other binding sites of the GABAA-R. To test whether behavioral effects of muscimol correlated with the density of high-affinity 3 Hmuscimol binding, we examined several GABA A-R subunit gene-modified mouse lines: α1, α4, or-knockouts (KO), α4-double KO, and Thy1.2 promoter-driven α6 transgenic mice (Thy1α6). We determined the high-affinity 3 Hmuscimol binding in brain sections by quantitative autoradiography and sedative/ataxic effects induced in vivo by muscimol using a constant speed rotarod. α4-KO mice had reduced 3 Hmuscimol binding in the caudate-putamen, thalamus, and hippocampus, and were less sensitive to the behavioral impairment by muscimol. Similarly,-KO mice also had reduced binding to forebrain regions and a lower behavioral sensitivity to muscimol than their wild-type controls. In contrast, α1-KO mice had unaltered behavioral sensitivity to muscimol and unaltered 3 Hmuscimol binding, even though previous studies have demonstrated dramatically reduced binding to various other GABAA-R sites in these mice. Finally, Thy1α6 mice exhibited increased behavioral sensitivity to muscimol, and to another direct GABA-site agonist gaboxadol, and increased 3 Hmuscimol binding in the cerebral cortex and hippocampus. Thus, the differences in sedative and motor-impairing actions of muscimol in various mouse models correlated with the level of forebrain high-affinity 3 Hmuscimol binding. These data suggest that a small special population of GABAA-Rs, most likely extrasynaptic non-α1-containing receptors, strongly contributes to the in vivo pharmacological effects of muscimol.

Original languageEnglish (US)
Pages (from-to)999-1007
Number of pages9
JournalNeuropsychopharmacology
Volume35
Issue number4
DOIs
StatePublished - Mar 2010
Externally publishedYes

Keywords

  • Extrasynaptic receptors
  • GABA type A receptor
  • Gaboxadol
  • Gene knockout mice
  • Muscimol
  • Transgenic mice

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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