June H L, Devaraju S L, Eggers M W, Williams J A, Cason C R, Greene T L, Leveige T, Braun M R, Torres L, Murphy J M
Department of Psychology, Indiana University School of Medicine, Indiana University-Purdue University, Indianapolis 46202-3275, USA.
Eur J Pharmacol. 1998 Jan 26;342(2-3):139-51. doi: 10.1016/s0014-2999(97)01489-1.
The pyrazoloquinoline CGS 8216 (2-phenylpyrazolo-[4,3-c]-quinolin-3 (5H)-one, 0.05-2 mg/kg) and the beta-carboline ZK 93426 (ethyl-5-isopropyl-4-methyl-beta-carboline-3-carboxylate, 1-10 mg/kg) benzodiazepine receptor antagonists were evaluated for their capacity to modulate the behavioral actions of ethanol in alcohol preferring and -nonpreferring rats. When alcohol-preferring rats were presented with a two-bottle choice test between ethanol (10% v/v) and a saccharin (0.0125% g/v) solution, both antagonists dose-dependently reduced intake of ethanol by 35-92% of control levels on day 1 at the initial 15 min interval of the 4 h limited access. Saccharin drinking was suppressed only with the highest doses. CGS 8216 (0.25 mg/kg) and ZK 93426 (4 mg/kg) unmasked the anxiolytic effects of a hypnotic ethanol dose (1.5 g/kg ethanol) on the plus maze test in alcohol-preferring rats, but potentiated the ethanol-induced suppression in alcohol-nonpreferring rats. CGS 8216 (0.25 mg/kg) and ZK 93426 (4 mg/kg) attenuated the ethanol (0.5 and 1.5 g/kg)-induced suppression in the open field in alcohol-nonpreferring rats; however, CGS 8216 potentiated the depressant effects of the lower ethanol dose (0.5 g/kg) in alcohol-preferring rats. These findings provide evidence that benzodiazepine receptor antagonists may differentially modulate the behavioral actions of ethanol in alcohol-preferring and-nonpreferring rats. It is possible that the qualitative pharmacodynamic differences seen in the present study may be related to selective breeding for alcohol preference. The findings indicate the potential for development of receptor specific ligands devoid of toxic effects which may be useful in the treatment of alcohol abuse and alcoholism.
对吡唑并喹啉CGS 8216（2-苯基吡唑并-[4,3-c]-喹啉-3（5H）-酮，0.05-2毫克/千克）和β-咔啉ZK 93426（乙基-5-异丙基-4-甲基-β-咔啉-3-羧酸盐，1-10毫克/千克）这两种苯二氮䓬受体拮抗剂调节嗜酒和非嗜酒大鼠乙醇行为效应的能力进行了评估。在给嗜酒大鼠提供乙醇（10% v/v）和糖精（0.0125% g/v）溶液之间的双瓶选择试验时，在4小时限时摄入的最初15分钟间隔内，第1天这两种拮抗剂均剂量依赖性地使乙醇摄入量减少至对照水平的35-92%。仅在最高剂量时糖精饮用量受到抑制。CGS 8216（0.25毫克/千克）和ZK 93426（4毫克/千克）在嗜酒大鼠的高架十字迷宫试验中揭示了催眠剂量乙醇（1.5克/千克乙醇）的抗焦虑作用，但在非嗜酒大鼠中增强了乙醇诱导的抑制作用。CGS 8216（0.25毫克/千克）和ZK 93426（4毫克/千克）减弱了非嗜酒大鼠在旷场试验中乙醇（0.5和1.5克/千克）诱导的抑制作用；然而，CGS 8216增强了嗜酒大鼠中较低剂量乙醇（0.5克/千克）的抑制作用。这些发现证明苯二氮䓬受体拮抗剂可能对嗜酒和非嗜酒大鼠的乙醇行为效应产生不同的调节作用。本研究中观察到的定性药效学差异可能与对酒精偏好的选择性育种有关。这些发现表明有可能开发出无毒副作用的受体特异性配体，这可能对治疗酒精滥用和酒精中毒有用。
