Uusi-Oukari M, Korpi E R
University of Tampere, Department of Biomedical Sciences, Finland.
Alcohol Clin Exp Res. 1991 Mar;15(2):241-8. doi: 10.1111/j.1530-0277.1991.tb01864.x.
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 GABAA 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 [3H]muscimol binding sites in the cerebellum than the alcohol-sensitive ANT rats. The cerebellar "diazepam-insensitive" [3H]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" [3H]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 [3H]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 [3H]muscimol binding or in the sensitivity of [3H]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).(ABSTRACT TRUNCATED AT 250 WORDS)
AT（耐酒精）和ANT（不耐酒精）大鼠品系是因对乙醇急性运动损害作用的敏感性不同而选育出来的，研究表明它们小脑GABAA受体的配体结合特性存在差异。在本研究中，我们进一步表征了这些结合差异，并确定在因乙醇敏感性差异而通过选择性育种产生的其他啮齿动物品系对中是否存在类似差异。对酒精不敏感的AT大鼠小脑内的高亲和力[3H]蝇蕈醇结合位点比酒精敏感的ANT大鼠更多。小脑“地西泮不敏感”的[3H]Ro 15 - 4513结合位点在微摩尔浓度下可被几种苯二氮䓬激动剂（地西泮、劳拉西泮、氯硝西泮和咪达唑仑）取代，在ANT大鼠中的效力高于AT大鼠。对取代曲线的分析表明，“地西泮不敏感”的[3H]Ro 15 - 4513结合位点对苯二氮䓬激动剂的亲和力在ANT大鼠中比AT大鼠高30至300倍。在弱部分激动剂Ro 15 - 1788、部分反向激动剂Ro 15 - 4513或外周型苯二氮䓬受体配体Ro 5 - 4864的取代效力方面，大鼠品系之间没有差异。因此，小脑[3H]Ro 15 - 4513结合位点中观察到的亲和力差异似乎对苯二氮䓬激动剂具有特异性。这种亲和力差异可能解释了大鼠品系对劳拉西泮敏感性的行为差异。在所测试的其他啮齿动物品系对（LS/SS、HAS/LAS、HOT/COLD、FAST/SLOW、AA/ANA）之间，未发现[3H]蝇蕈醇结合或[3H]Ro 15 - 4513结合对微摩尔浓度地西泮敏感性的差异。（摘要截于250字）
