Prototypic GABA(A) receptor agonist muscimol acts preferentially through forebrain high-affinity binding sites.
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.
Chandra
Dev
D
Departments of Anesthesiology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Halonen
Lauri M
LM
Linden
Anni-Maija
AM
Procaccini
Chiara
C
Hellsten
Kati
K
Homanics
Gregg E
GE
Korpi
Esa R
ER
D000818:Animals; D001345:Autoradiography / Q000379:methods; D001665:Binding Sites / Q000187:drug effects* / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009118:Muscimol / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics; D011963:Receptors, GABA-A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D018755:GABA Agonists; D021122:Protein Subunits; D011963:Receptors, GABA-A; D014316:Tritium; D009118:Muscimol