Parkes H, Sinclair J D
Department of Mental Health and Alcohol Research, National Public Health Institute, POB 719, FIN-00101, Helsinki, Finland.
Alcohol. 2000 Jul;21(3):215-21. doi: 10.1016/s0741-8329(00)00091-4.
Rats of the high-drinking AA line were given 1 mg/kg naltrexone (NTX) or vehicle orally with a stress-free procedure just before 1 h of access to 10% ethanol daily for 8 days and again, 8 h later on the first 7 days. Forebrain homogenate binding studies using 0.03-6.00 nM [3H] naloxone were conducted from 1 to 4 days following treatment. NTX significantly suppressed alcohol intake, with the effect becoming progressively greater over days and continuing during the post-treatment period. Saturation binding studies in brain homogenate revealed that NTX had increased the B(max) for opioid receptors by 93%, 74%, 49%, and 28%, respectively, from post-treatment days 1 to 4 without altering K(d). B(max) was negatively correlated (r=-0.510, p=0.008) with alcohol intake during the preceding hour, but in control rats, it was positively correlated with changes in alcohol intake over time (r=+0.790, p=0.020). These results are consistent with the hypothesis that opioid receptors mediate reinforcement from alcohol and that NTX reduces subsequent alcohol drinking by extinction. Opioid receptor upregulation can develop simultaneously with suppression of drinking and may partially counteract the clinical benefits from NTX in the treatment of alcoholism.
在高饮酒量的AA系大鼠每天获取10%乙醇前1小时，通过无应激程序给它们口服1 mg/kg纳曲酮（NTX）或赋形剂，持续8天，且在第1至7天，8小时后再次给药。在治疗后的第1至4天，使用0.03 - 6.00 nM [3H]纳洛酮进行前脑匀浆结合研究。NTX显著抑制了酒精摄入量，且这种作用随时间逐渐增强，并在治疗后阶段持续存在。脑匀浆中的饱和结合研究表明，从治疗后第1至4天，NTX使阿片受体的最大结合容量（B(max)）分别增加了93%、74%、49%和28%，而解离常数（K(d)）未改变。B(max)与前一小时的酒精摄入量呈负相关（r = -0.510，p = 0.008），但在对照大鼠中，它与酒精摄入量随时间的变化呈正相关（r = +0.790，p = 0.020）。这些结果与阿片受体介导酒精强化作用以及NTX通过消退作用减少后续酒精摄入的假设一致。阿片受体上调可与饮酒抑制同时发生，并可能部分抵消NTX在治疗酒精中毒方面的临床益处。
