Witkin J M, Acri J B, Gleeson S, Barrett J E
Addiction Research Center, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.
Pharmacol Biochem Behav. 1997 Jan;56(1):1-7. doi: 10.1016/S0091-3057(96)00120-7.
Benzodiazepine receptor partial agonists manifest full efficacy in preclinical tests of anxiolytic drug action but do not fully reproduce the discriminative stimulus effects of benzodiazepine receptor full agonists in pigeons. The partial agonist, bretazenil, binds to both diazepam-sensitive and diazepam-insensitive GABAA receptors. Previous studies have suggested a role for each of these receptor populations in some behavioral effects of bretazenil in pigeons. A possible role for these receptor subtypes in the behavioral effects of bretazenil was further investigated through drug interaction studies with the benzodiazepine receptor antagonists, flumazenil and ZK 93,426. Whereas flumazenil binds with high affinity to both receptor isoforms, ZK 93,426 binds preferentially to diazepam-sensitive binding sites. Bretazenil markedly increased punished responding of pigeons without significantly affecting nonpunished responding. In pigeons discriminating the full benzodiazepine receptor agonist, midazolam, from saline, bretazenil produced only 60-75% maximal effect. Flumazenil and ZK 93,426 neither increased punished responding nor substituted for midazolam, but dose-dependently blocked the effects of bretazenil on punished responding. Flumazenil also dose-dependently blocked the effects of bretazenil in midazolam-discriminating pigeons, whereas ZK 93,426 only attenuated this effect. These results indicate that bretazenil's actions as a partial agonist at diazepam-sensitive benzodiazepine receptors mediate increases in punished responding and substitution for the discriminative stimulus effects of midazolam in pigeons. The differences in the effects of flumazenil and ZK 93,426 on the discriminative stimulus effects of bretazenil suggest a potential contribution of diazepam-insensitive sites to this behavioral effect.
苯二氮䓬受体部分激动剂在抗焦虑药物作用的临床前试验中表现出完全疗效，但不能完全重现苯二氮䓬受体完全激动剂在鸽子中的辨别性刺激效应。部分激动剂布雷替奈酯可与对苯二氮䓬敏感和不敏感的GABAA受体结合。先前的研究表明，这些受体群体中的每一个在布雷替奈酯对鸽子的某些行为效应中都起作用。通过与苯二氮䓬受体拮抗剂氟马西尼和ZK 93426进行药物相互作用研究，进一步探究了这些受体亚型在布雷替奈酯行为效应中的可能作用。氟马西尼与两种受体亚型均具有高亲和力结合，而ZK 93426则优先与对苯二氮䓬敏感的结合位点结合。布雷替奈酯显著增加了鸽子的受罚反应，而对未受罚反应没有显著影响。在辨别完全苯二氮䓬受体激动剂咪达唑仑和生理盐水的鸽子中，布雷替奈酯仅产生60%-75%的最大效应。氟马西尼和ZK 93426既没有增加受罚反应，也不能替代咪达唑仑，但剂量依赖性地阻断了布雷替奈酯对受罚反应的影响。氟马西尼还剂量依赖性地阻断了布雷替奈酯在辨别咪达唑仑的鸽子中的效应，而ZK 93426仅减弱了这种效应。这些结果表明，布雷替奈酯作为对苯二氮䓬敏感的苯二氮䓬受体部分激动剂的作用介导了鸽子受罚反应的增加以及对咪达唑仑辨别性刺激效应的替代。氟马西尼和ZK 93426对布雷替奈酯辨别性刺激效应的影响差异表明，对苯二氮䓬不敏感的位点对这种行为效应有潜在贡献。
