Prototypic GABA(A) receptor agonist muscimol acts preferentially through forebrain high-affinity binding sites

Neuropsychopharmacology. 2010 Mar;35(4):999-1007. doi: 10.1038/npp.2009.203. Epub 2009 Dec 23.


Muscimol has been regarded as a universal agonist for all gamma-aminobutyric acid type A receptor (GABA(A)-R) subtypes. However, brain regional distribution of muscimol's high-affinity binding sites greatly differs from those of other binding sites of the GABA(A)-R. To test whether behavioral effects of muscimol correlated with the density of high-affinity [(3)H]muscimol binding, we examined several GABA(A)-R subunit gene-modified mouse lines: alpha1, alpha4, or delta-knockouts (KO), alpha4+delta-double KO, and Thy1.2 promoter-driven alpha6 transgenic mice (Thy1alpha6). We determined the high-affinity [(3)H]muscimol binding in brain sections by quantitative autoradiography and sedative/ataxic effects induced in vivo by muscimol using a constant speed rotarod. alpha4-KO mice had reduced [(3)H]muscimol binding in the caudate-putamen, thalamus, and hippocampus, and were less sensitive to the behavioral impairment by muscimol. Similarly, delta-KO mice also had reduced binding to forebrain regions and a lower behavioral sensitivity to muscimol than their wild-type controls. In contrast, alpha1-KO mice had unaltered behavioral sensitivity to muscimol and unaltered [(3)H]muscimol binding, even though previous studies have demonstrated dramatically reduced binding to various other GABA(A)-R sites in these mice. Finally, Thy1alpha6 mice exhibited increased behavioral sensitivity to muscimol, and to another direct GABA-site agonist gaboxadol, and increased [(3)H]muscimol 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)H]muscimol binding. These data suggest that a small special population of GABA(A)-Rs, most likely extrasynaptic non-alpha1-containing receptors, strongly contributes to the in vivo pharmacological effects of muscimol.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoradiography / methods
  • Binding Sites / drug effects*
  • Binding Sites / genetics
  • Exploratory Behavior / drug effects
  • GABA Agonists / pharmacology*
  • Mice
  • Mice, Transgenic
  • Muscimol / pharmacology*
  • Prosencephalon / drug effects*
  • Prosencephalon / metabolism
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Protein Subunits / deficiency
  • Protein Subunits / genetics
  • Receptors, GABA-A / deficiency
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Time Factors
  • Tritium / pharmacokinetics


  • GABA Agonists
  • Protein Subunits
  • Receptors, GABA-A
  • Tritium
  • Muscimol