title: Cerebellar GABAA receptors in two rat lines selected for high and low sensitivity to moderate alcohol doses: pharmacological and genetic studies.
abstract: Alcohol-sensitive (ANT) rat line produced by selective outbreeding for high acute sensitivity to the motor-impairing effects of ethanol, displays unusual cerebellar GABAA receptor pharmacology. The ANT rats have enhanced benzodiazepine agonist affinity at their binding sites for an imidazobenzodiazepine, [3H]Ro 15-4513, normally not affected by agonists at all, and reduced GABAA agonist, [3H]muscimol, binding, when compared to the alcohol-insensitive (AT) rat line. In the present study, the benzodiazepine receptor difference was localized to the cerebellar granule cell layer. This receptor difference was not found in ex vivo binding studies after lorazepam administration, although brain lorazepam concentrations in both rat lines similarly exceeded 1 microM. An indication for differential binding in vivo between the lines was, however, observed, as pretreatment with lorazepam accentuated the relative accumulation of radioactivity only in the cerebellum of the AT rat line after an intravenous injection of a trace amount of [3H]Ro 15-4513, thus revealing benzodiazepine insensitivity for a portion of the cerebellar [3H]Ro 15-4513 binding in the AT but not in the ANT rats. In the second generation of AT/ANT cross-breeding, there was no clear association of alcohol sensitivity and cerebellar receptor binding. There was, however, a significant positive correlation between the [3H]muscimol binding and the diazepam-insensitive [3H]Ro 15-4513 binding in the cerebellum. In conclusion, the receptor defect in the cerebellar granular cell layer of the alcohol-sensitive ANT rats was also detectable in vivo, but it may not explain the enhanced alcohol sensitivity of these rats.
authors.affiliation: Research Laboratories, Alko Ltd., Helsinki, Finland.
authors.forename: E R
authors.initials: ER
authors.lastname: Korpi
authors.forename: M
authors.initials: M
authors.lastname: Uusi-Oukari
authors.forename: E
authors.initials: E
authors.lastname: Castren
authors.forename: P D
authors.initials: PD
authors.lastname: Suzdak
authors.forename: T
authors.initials: T
authors.lastname: Seppälä
authors.forename: M
authors.initials: M
authors.lastname: Sarviharju
authors.forename: K
authors.initials: K
authors.lastname: Tuominen
mesh_terms: D000818:Animals; D001345:Autoradiography; D001386:Azides / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D000431:Ethanol / Q000494:pharmacology*; D008140:Lorazepam / Q000493:pharmacokinetics / Q000494:pharmacology; D009118:Muscimol / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D001386:Azides; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D009118:Muscimol; D000431:Ethanol; C042957:Ro 15-4513; D008140:Lorazepam