Pharmacologic actions of subtype-selective and novel GABAergic ligands in rat lines with differential sensitivity to ethanol.
Alcohol-nontolerant (ANT) rats, produced by selective breeding for high sensitivity to motor-impairing effects of ethanol, have a point mutation in the cerebellar gamma-aminobutyric acid type A (GABAA) receptor alpha 6 subunit, which has been proposed to underlie enhanced sensitivity to benzodiazepine agonists as well. We compared ANT and alcohol-tolerant (AT) rats using behavioral and neurochemical methods to assess the significance of alpha 6- and non alpha 6-containing GABAA receptor subtypes. Motor performance in a tilting plane test was largely unaffected by a type I benzodiazepine receptor-preferring agonist, zolpidem [1-10 mg/kg, intraperitoneally (IP)], partial benzodiazepine agonists bretazenil and ZG-63 (both at 40 mg/kg, IP), and a novel broad-spectrum anticonvulsant loreclezole (40 mg/kg, IP) in both ANT and AT rats. In contrast, diazepam (10 mg/kg, IP) impaired performance of the ANT but not AT animals. These data, supported by results from brain regional autoradiography of [3H]Ro15-4513 and membrane binding of [3H]ZG-63 and [35S]TBPS as influenced by these ligands, strongly suggest that only ligands with full agonist actions on mutant (ANT) but not wild-type (AT) alpha 6-containing GABAA receptors are able to produce motor impairment in the ANT rats.
Wong
G
G
Biomedical Research Center, Alko Group Ltd., Helsinki, Finland.
Sarviharju
M
M
Toropainen
M
M
Matecka
D
D
Korpi
E R
ER
D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D014230:Triazoles / Q000494:pharmacology; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D006993:Hypnotics and Sedatives; D011725:Pyridines; D014230:Triazoles; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; C066440:loreclezole; D000077334:Zolpidem; D003975:Diazepam