GABAA receptors containing ρ1 subunits contribute to in vivo effects of ethanol in mice.
GABAA receptors containing ρ1 subunits contribute to in vivo effects of ethanol in mice.
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DOI：
10.1371/journal.pone.0085525
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Harris RA
中科院分区：
文献类型：
--
作者：
Blednov YA;Benavidez JM;Black M;Leiter CR;Osterndorff-Kahanek E;Johnson D;Borghese CM;Hanrahan JR;Johnston GA;Chebib M;Harris RA
GABAA受体由同源或异五聚体中的ρ1， ρ2或ρ3亚基组成，主要在视网膜中被研究，但在许多脑区也被检测到。由ρ1形成的受体受到低乙醇浓度的抑制，基于家族的关联分析将ρ亚基基因与酒精依赖联系起来。我们确定小鼠中基因缺失的ρ1是否会改变体内乙醇效应。零突变雄性小鼠在两瓶选择测试中表现出减少的乙醇消耗和偏好，对糖精或奎宁的偏好没有差异。两性零突变小鼠均表现出乙醇诱导的翻正反射（LORR）丧失持续时间更长，雄性小鼠对乙醇诱导的运动镇静更敏感。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。零突变雌性对乙醇诱导的条件性味觉厌恶的发展不太敏感。小脑mRNA水平测定显示，缺失ρ1未改变ρ2、α2、α6 GABAA受体亚基的表达。(S)-4-氨基-环戊烯-1-烯基丁基膦酸（“ρ1”拮抗剂），当给予野生型小鼠时，模仿乙醇在ρ1无效小鼠（LORR和rotarod试验）中诱导的变化，但ρ1拮抗剂在ρ1无效小鼠中没有产生这些作用。相反，(R)-4-氨基-环戊烯-1-烯基丁基膦酸（“ρ2”拮抗剂）在野生型中不改变乙醇的作用，但在缺乏ρ1的小鼠中产生的作用与删除（或抑制）ρ1的作用相反。这些结果表明，在乙醇的两种体内效应中，ρ1具有主导作用，当ρ1缺失时，可能揭示了ρ2的作用。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受体的作用可能是乙醇在体内产生特异性作用的重要原因。
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.
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DOI：
10.1124/jpet.103.049478
发表时间：
2003-06-01
影响因子：
3.5
作者：
Blednov, YA;Walker, D;Harris, RA
通讯作者：
Harris, RA
DOI：
10.1124/jpet.106.104406
发表时间：
2006-10-01
影响因子：
3.5
作者：
Borghese, C. M.;Werner, D. F.;Harrison, N. L.
通讯作者：
Harrison, N. L.
DOI：
10.1124/jpet.108.146464
发表时间：
2009-02
影响因子：
3.5
作者：
Chebib, Mary;Hinton, Tina;Schmid, Katrina L.;Brinkworth, Darren;Qian, Haohua;Matos, Susana;Kim, Hye-Lim;Abdel-Halim, Heba;Kumar, Rohan J.;Johnston, Graham A. R.;Hanrahan, Jane R.
通讯作者：
Hanrahan, Jane R.
DOI：
10.1124/jpet.111.185124
发表时间：
2012-02-01
影响因子：
3.5
作者：
Blednov, Yuri A.;Benavidez, Jill M.;Harris, R. Adron
通讯作者：
Harris, R. Adron
DOI：
10.1016/j.molbrainres.2005.03.013
发表时间：
2005-07-29
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Fujimura, J;Nagano, M;Suzuki, H
通讯作者：
Suzuki, H