Grech D M, Balster R L
Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613, USA.
Psychopharmacology (Berl). 1997 Feb;129(4):339-47.
To evaluate the discriminative stimulus effects of a direct-acting GABAA agonist, seven rats were trained to discriminate 1 mg/kg IP muscimol from saline under a two-lever fixed ratio (FR) 20 schedule of food reinforcement. The direct GABAA agonist THIP (4,5,6,7-tetrahydro-isoxazolo [5, 4,c]-pyridin-3-ol) produced increases in muscimol lever responding and substituted for muscimol in all subjects. Unlike results with muscimol, the highest levels of muscimol lever responding following THIP administration were often produced at doses which also decreased rates of responding. The GABAB agonist baclofen and the indirect-acting GABAA agonists pentobarbital and midazolam produced substitution for muscimol in some subjects, but not in others. The non-competitive NMDA antagonist phencyclidine (PCP) produced mixed results in these rats, from partial to full substitution (both dose-dependently and exhibiting in lack of dose-dependence) in some animals and a complete failure to substitute in another. The selective GABAA antagonist bicuculline dose-dependently blocked the muscimol discriminative stimulus in a majority of subjects. This study is the first report of successful training of a drug discrimination in rats using muscimol. Evidence is provided from substitution and antagonism testing with THIP and bicuculline, respectively, that the muscimol discrimination was mediated by actions at the GABA binding site on the GABAA receptor-ionophore complex. Results, also suggest that drug stimulus control by muscimol is weak compared to that of other types of GABA agonists previously studied using drug discrimination procedures in rodents.
为评估一种直接作用的GABAA激动剂的辨别刺激效应，七只大鼠在双杠杆固定比率（FR）20食物强化程序下接受训练，以区分1mg/kg腹腔注射的蝇蕈醇和生理盐水。直接的GABAA激动剂THIP（4,5,6,7-四氢异恶唑并[5,4,c]-吡啶-3-醇）使所有受试动物对蝇蕈醇杠杆的反应增加，并能替代蝇蕈醇。与蝇蕈醇的结果不同，给予THIP后，蝇蕈醇杠杆反应的最高水平通常出现在也会降低反应率的剂量下。GABAB激动剂巴氯芬以及间接作用的GABAA激动剂戊巴比妥和咪达唑仑在一些受试动物中能替代蝇蕈醇，但在另一些动物中则不能。非竞争性NMDA拮抗剂苯环己哌啶（PCP）在这些大鼠中产生了混合结果，在一些动物中部分至完全替代（剂量依赖性和非剂量依赖性均有表现），而在另一只动物中则完全不能替代。选择性GABAA拮抗剂荷包牡丹碱在大多数受试动物中剂量依赖性地阻断了蝇蕈醇的辨别刺激。本研究是首次报道在大鼠中使用蝇蕈醇成功训练药物辨别。分别通过THIP和荷包牡丹碱的替代和拮抗试验提供的证据表明，蝇蕈醇辨别是由其在GABAA受体-离子通道复合物上的GABA结合位点的作用介导的。结果还表明，与先前在啮齿动物中使用药物辨别程序研究的其他类型GABA激动剂相比，蝇蕈醇对药物刺激的控制较弱。
