Effects of a novel uncompetitive NMDA receptor antagonist, MRZ 2/579 on ethanol self-administration and ethanol withdrawal seizures in the rat
Effects of a novel uncompetitive NMDA receptor antagonist, MRZ 2/579 on ethanol self-administration and ethanol withdrawal seizures in the rat
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DOI：
10.1016/s0014-2999(01)00743-9
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发表时间：
2001-02-09
影响因子：
5
通讯作者：
Danysz, W
中科院分区：
文献类型：
--
作者：
Bienkowski, P;Krzascik, P;Danysz, W
NMDA受体在乙醇诱导的辨别性刺激效应和戒断综合征中的作用已被多次报道，但NMDA受体在乙醇强化效应中的作用尚不清楚。本研究的目的是评估新型低亲和力、非竞争性NMDA受体拮抗剂的作用。1-氨基-1，3，3，5，5-五甲基环己烷盐酸盐（MRZ 2/579）对大鼠乙醇自我给药和乙醇戒断相关癫痫发作的影响。采用操作性（杠杆按压乙醇）和非操作性两瓶选择设置启动乙醇自我给药。在另一个程序中。使用高剂量（9-15 g/kg/天）的强制处理来诱导对乙醇的身体依赖。MRZ 2/579通过渗透微泵长期给药（9.6 mg/天，s.c.）在乙醇自我给药的维持阶段，不改变操作性或非操作性乙醇饮用行为。相比之下，每天重复注射药物（5 mg/kg，i. p.）导致对乙醇的操作性反应逐渐减少。MRZ 2/579（0.5-7.5 mg/kg，i.p.）和另一种低亲和力NMDA受体拮抗剂美金刚（1-10 mg/kg，i. p.）剂量依赖性地抑制乙醇戒断发作，其效力与标准苯二氮卓衍生物地西泮相当。本研究的结果表明：（i）MRZ 2/579间歇给药可能导致乙醇的操作性反应逐渐降低;（ii）低亲和力非竞争性NMDA受体拮抗剂组可能是苯二氮卓类药物治疗酒精戒断的一种有趣的替代方案。(C)2001 Elsevier science B. V.保留所有权利。
It has been repeatedly reported that NMDA receptors may contribute to ethanol-induced discriminative stimulus effects and withdrawal syndrome, However, the role of NMDA receptors in the reinforcing properties of ethanol remains unclear. The aim of the present study was to evaluate effects of the novel low-affinity, uncompetitive NMDA receptor antagonist. 1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride (MRZ 2/579), on ethanol self-administration and ethanol withdrawal-associated seizures in rats. Both an operant (lever pressing for ethanol) and non-operant two-bottle choice setups were employed to initiate ethanol self-administration. In another procedure. forced treatment with high doses (9-15 g/kg/day) was used to induce physical dependence on ethanol. MRZ 2/579 delivered chronically by osmotic minipumps (9.6 mg/day, s.c.) did not alter either operant or non-operant ethanol drinking behaviour in a maintenance phase of ethanol self-administration. In contrast, repeated daily injections of the drug (5 mg/kg, i.p.) led to a progressive decrease in operant responding for ethanol. MRZ 2/579 (0.5-7.5 mg/kg, i.p.) and another low-affinity NMDA receptor antagonist, memantine(1-10 mg/kg, i.p.) dose-dependently suppressed ethanol withdrawal seizures with efficacies comparable with that of a standard benzodiazepine derivative, diazepam. The results of the present study indicate that: (i) intermittent administration of MRZ 2/579 may lead to a gradual decrease of operant responding for ethanol: and (ii) the group of low-affinity uncompetitive NMDA receptor antagonists may be an interesting alternative to benzodiazepines in the treatment of alcohol withdrawal. (C) 2001 Elsevier science B.V. All rights reserved.