Shannon Erin E, Shelton Keith L, Vivian Jeffrey A, Yount Ingrid, Morgan Ashley R, Homanics Gregg E, Grant Kathleen A
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
Alcohol Clin Exp Res. 2004 Jun;28(6):906-13. doi: 10.1097/01.alc.0000128227.28794.42.
Genetically altered mice have been used to examine gene contributions to ethanol phenotypes. Recently, mice with a targeted deletion of the delta subunit of the gamma-aminobutyric acid (GABA)A receptor have been generated. These mice display decreased sensitivity to neuroactive steroids and altered responses to some behavioral effects of ethanol. Given the application of drug discrimination to characterize receptor-mediated stimulus effects of ethanol and given the data showing altered ethanol responses in mice lacking the delta subunit of the GABAA receptor, these mice were characterized in an ethanol-discrimination procedure. It has been shown that neurosteroids will substitute for the discriminative stimulus effects of ethanol, and this study aimed to determine whether the substitution patterns of neuroactive steroids or other GABAA-positive modulators would be altered in these mice.
Twelve adult delta +/+ and delta-/- mice were trained to discriminate between ethanol 1.5 g/kg and saline in daily 15-min food-reinforced operant sessions. Once the discrimination was trained, substitution tests with ethanol, pentobarbital, midazolam, androsterone, alphaxalone, pregnanolone, morphine, zolpidem, and MK-801 were conducted.
Both delta+/+ and delta-/- mice acquired ethanol discrimination in a similar number of days. Ethanol, midazolam, alphaxalone, pregnanolone, and MK-801 fully substituted (>80%) for ethanol in both delta+/+ and delta-/- mice. Pentobarbital fully substituted for ethanol in delta-/- mice but only partially substituted (74%) for ethanol in delta+/+ mice. Androsterone, zolpidem, and morphine did not substitute for ethanol in either delta+/+ or delta-/- mice. There were no significant differences in the response rate-suppressing effects of any of the compounds between delta+/+ and delta-/- mice.
The training dose of ethanol resulted in substitution of five GABAA receptor ligands, indicating a robust GABAA mediation of ethanol's discriminative stimulus effects. Deletion of the delta subunit of the GABAA receptor does not alter the acquisition of an ethanol/saline discrimination or the substitution patterns of GABAA-positive modulators. Therefore, the delta subunit is not necessary in the mediation of ethanol-like effects of any of the GABAA ligands tested, including sensitivity to ethanol, barbiturate, benzodiazepine, and neurosteroid discriminative stimulus effects.
基因改造小鼠已被用于研究基因对乙醇表型的影响。最近，已培育出γ-氨基丁酸（GABA）A受体δ亚基靶向缺失的小鼠。这些小鼠对神经活性甾体的敏感性降低，对乙醇的某些行为效应的反应也发生改变。鉴于药物辨别用于表征乙醇的受体介导的刺激效应，且有数据显示缺乏GABAA受体δ亚基的小鼠的乙醇反应发生改变，因此对这些小鼠进行了乙醇辨别程序的表征。研究表明神经甾体可替代乙醇的辨别刺激效应，本研究旨在确定这些小鼠中神经活性甾体或其他GABAA阳性调节剂的替代模式是否会发生改变。
12只成年δ+/+和δ-/-小鼠在每天15分钟的食物强化操作性实验中接受训练，以区分1.5 g/kg乙醇和生理盐水。一旦训练出辨别能力，就用乙醇、戊巴比妥、咪达唑仑、雄甾酮、α-香附酮、孕烷醇酮、吗啡、唑吡坦和MK-801进行替代试验。
δ+/+和δ-/-小鼠在相似天数内都学会了乙醇辨别。在δ+/+和δ-/-小鼠中，乙醇、咪达唑仑、α-香附酮、孕烷醇酮和MK-801都能完全替代（>80%）乙醇。戊巴比妥在δ-/-小鼠中能完全替代乙醇，但在δ+/+小鼠中只能部分替代（74%）乙醇。雄甾酮、唑吡坦和吗啡在δ+/+或δ-/-小鼠中都不能替代乙醇。δ+/+和δ-/-小鼠之间，任何化合物的反应率抑制效应均无显著差异。
乙醇的训练剂量导致5种GABAA受体配体的替代，表明乙醇的辨别刺激效应有强大的GABAA介导作用。GABAA受体δ亚基的缺失不会改变乙醇/生理盐水辨别的习得，也不会改变GABAA阳性调节剂的替代模式。因此，在介导所测试的任何GABAA配体的类乙醇效应（包括对乙醇、巴比妥酸盐、苯二氮䓬和神经甾体辨别刺激效应的敏感性）中，δ亚基并非必需。
