SPECIFIC ALTERATIONS IN THE CEREBELLAR GABA(A) RECEPTORS OF AN ALCOHOL-SENSITIVE ANT RAT LINE

The AT (alcohol-tolerant) and ANT (alcohol-nontolerant) rat lines, selected for differential sensitivity to the acute motor-impairing effects of ethanol, have been shown to differ in the ligand binding characteristics of their cerebellar GABA(A) receptors. In the present study, we characterized these binding differences further and determined whether similar differences are present in other rodent line pairs produced by selective breeding for differences in ethanol sensitivity. The alcohol-insensitive AT rats had more high-affinity [H-3]muscimol binding sites in the cerebellum than the alcohol-sensitive ANT rats. The cerebellar "diazepam-insensitive" [H-3]Ro 15-4513 binding sites were displaced by several benzodiazepine agonists (diazepam, lorazepam, clonazepam, and midazolam) at micromolar concentrations with greater efficacy in the ANT than the AT rats. Analyses of the displacement curves indicated that the "diazepam-insensitive" [H-3] Ro 15-4513 binding sites have 30 to 300 times higher affinity to benzodiazepine agonists in the ANT than AT rats. There was no difference between the rat lines in the displacing potency of Ro 15-1788, a weak partial agonist; Ro 15-4513, a partial inverse agonist; or Ro 5-4864, a peripheral-type benzodiazepine receptor ligand. Thus, the affinity difference seen in the cerebellar [H-3]Ro 15-4513 binding sites seems to be specific for benzodiazepine agonists. This difference in affinity may explain the behavioral difference in sensitivity to lorazepam between the rat lines. No differences in [H-3]muscimol binding or in the sensitivity of [H-3]Ro 15-4513 binding to micromolar diazepam concentrations were found between other rodent line pairs tested (LS/SS, HAS/LAS, HOT/COLD, FAST/SLOW, AA/ANA). The displacement of [H-3]Ro 15-4513 binding from the cerebellar membranes by diazepam was significantly greater in the ANT than in Mixed (M) rats (the starting population for the selection of the AT and ANT rats), whereas there was no difference in this displacement between the AT and M rats. Thus, the selection of the AT and ANT rats has produced an alcohol-sensitive ANT rat line with specific alterations in its cerebellar GABA(A) receptors.