Pharmacologic actions of subtype-selective and novel GABAergic ligands in rat lines with differential sensitivity to ethanol

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 1996-03, Vol.53 (3), p.723-730
• Main Authors: Wong, Garry, Sarviharju, Maija, Toropainen, Maija, Matecka, Dorota, Korpi, Esa R.
• Format: Article
• Language: English
• Subjects: Alcohol sensitivity; Alcoholism and acute alcohol poisoning; Animals; Autoradiography; Benzodiazepine receptors; Binding, Competitive; Biological and medical sciences; Bretazenil; Diazepam - pharmacology; Dose-Response Relationship, Drug; Ethanol - pharmacology; GABA A receptor subtypes; gamma-Aminobutyric Acid - pharmacology; Hypnotics and Sedatives - pharmacology; Loreclezole; Male; Medical sciences; Motor Activity - drug effects; Pyridines - pharmacology; Rats; Selected rat lines; Toxicology; Triazoles - pharmacology; ZG-63; Zolpidem
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/0091-3057(95)02076-4

Alcohol-nontolerant (ANT) rats, produced by selective breeding for high sensitivity to motor-impairing effects of ethanol, have a point mutation in the cerebellar γ-aminobutyric acid type A (GABA A) receptor α6 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 α6- and nonα6-containing GABA A 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) α6-containing GABA A receptors are able to produce motor impairment in the ANT rats.