Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America.
Faculty of Pharmacy, The University of Sydney, Sydney NSW, Australia.
PLoS One. 2014 Jan 16;9(1):e85525. doi: 10.1371/journal.pone.0085525. eCollection 2014.
GABAA receptors consisting of ρ1, ρ2, or ρ3 subunits in homo- or hetero-pentamers have been studied mainly in retina but are detected in many brain regions. Receptors formed from ρ1 are inhibited by low ethanol concentrations, and family-based association analyses have linked ρ subunit genes with alcohol dependence. We determined if genetic deletion of ρ1 in mice altered in vivo ethanol effects. Null mutant male mice showed reduced ethanol consumption and preference in a two-bottle choice test with no differences in preference for saccharin or quinine. Null mutant mice of both sexes demonstrated longer duration of ethanol-induced loss of righting reflex (LORR), and males were more sensitive to ethanol-induced motor sedation. In contrast, ρ1 null mice showed faster recovery from acute motor incoordination produced by ethanol. Null mutant females were less sensitive to ethanol-induced development of conditioned taste aversion. Measurement of mRNA levels in cerebellum showed that deletion of ρ1 did not change expression of ρ2, α2, or α6 GABAA receptor subunits. (S)-4-amino-cyclopent-1-enyl butylphosphinic acid ("ρ1" antagonist), when administered to wild type mice, mimicked the changes that ethanol induced in ρ1 null mice (LORR and rotarod tests), but the ρ1 antagonist did not produce these effects in ρ1 null mice. In contrast, (R)-4-amino-cyclopent-1-enyl butylphosphinic acid ("ρ2" antagonist) did not change ethanol actions in wild type but produced effects in mice lacking ρ1 that were opposite of the effects of deleting (or inhibiting) ρ1. These results suggest that ρ1 has a predominant role in two in vivo effects of ethanol, and a role for ρ2 may be revealed when ρ1 is deleted. We also found that ethanol produces similar inhibition of function of recombinant ρ1 and ρ2 receptors. These data indicate that ethanol action on GABAA receptors containing ρ1/ρ2 subunits may be important for specific effects of ethanol in vivo.
GABAA 受体由 ρ1、ρ2 或 ρ3 亚基组成，以同源或异源五聚体形式存在，已在视网膜中得到广泛研究，但在许多脑区也有发现。由 ρ1 组成的受体被低浓度乙醇抑制，基于家族的关联分析已将 ρ 亚基基因与酒精依赖联系起来。我们确定了在体内改变 ρ1 基因缺失是否会改变乙醇的作用。雄性 null 突变体小鼠在双瓶选择试验中表现出乙醇消耗和偏好减少，而对蔗糖或奎宁的偏好没有差异。雌雄两性 null 突变体小鼠的乙醇诱导的翻正反射丧失（LORR）持续时间更长，而雄性小鼠对乙醇诱导的运动镇静更为敏感。相比之下，ρ1 缺失小鼠从乙醇引起的急性运动不协调中恢复得更快。雌性 null 突变体小鼠对乙醇诱导的条件味觉厌恶的发展敏感性较低。小脑 mRNA 水平的测量显示，ρ1 的缺失并未改变 ρ2、α2 或 α6 GABAA 受体亚基的表达。(S)-4-氨基环戊-1-烯基丁基膦酸（“ρ1”拮抗剂）在给予野生型小鼠时，模拟了乙醇在 ρ1 缺失小鼠中诱导的变化（LORR 和转棒试验），但 ρ1 拮抗剂在 ρ1 缺失小鼠中没有产生这些作用。相比之下，(R)-4-氨基环戊-1-烯基丁基膦酸（“ρ2”拮抗剂）在野生型小鼠中没有改变乙醇的作用，但在缺失 ρ1 的小鼠中产生了与缺失（或抑制）ρ1 相反的作用。这些结果表明，ρ1 在乙醇的两种体内作用中起主要作用，而当 ρ1 缺失时，ρ2 的作用可能会显现出来。我们还发现，乙醇对重组 ρ1 和 ρ2 受体的功能产生类似的抑制作用。这些数据表明，乙醇对含有 ρ1/ρ2 亚基的 GABAA 受体的作用可能对乙醇在体内的特定作用很重要。
