Both GABA(B) receptor activation and blockade exacerbated anhedonic aspects of nicotine withdrawal in rats.
Both GABA(B) receptor activation and blockade exacerbated anhedonic aspects of nicotine withdrawal in rats.
复制标题
GABA(B) 受体激活和阻断都会加剧大鼠尼古丁戒断的快感缺失。
DOI：
10.1016/j.ejphar.2011.01.009
复制
发表时间：
2011
影响因子：
5
通讯作者：
Markou,Athina
中科院分区：
文献类型：
--
作者：
Vlachou,Styliani;Paterson,NeilE;Guery,Sebastien;Kaupmann,Klemens;Froestl,Wolfgang;Banerjee,Deboshri;Finn,MG;Markou,Athina
尼古丁依赖是由尼古丁戒断产生的令人厌恶的、类似抑郁的效应和急性尼古丁的奖赏效应维持的。GABA受体拮抗剂在啮齿动物中表现出类似于抗抑郁的作用，而GABA受体激动剂则减弱尼古丁的奖赏效应。最近对GABA受体阳性调节剂的研究表明，这些化合物比GABA受体激动剂副作用少，是治疗尼古丁依赖的潜在改进药物。因此，GABA受体激动剂和拮抗剂以及GABA受体正向调节剂可能通过靶向尼古丁依赖和戒断的不同方面而具有戒烟辅助作用。本研究评估了GABA受体激动剂CGP44532、GABA受体拮抗剂CGP56433A和GABA受体正向调节剂BHF177对尼古丁戒断的无快感方面的影响。采用下丘脑后外侧刺激电极制作大鼠模型。建立稳定的颅内自我刺激(ICSS)阈值后，皮下注射尼古丁或生理盐水微泵，连续7天或14天。在拔泵后6h评估ICSS阈值。泵取出30小时后，在ICSS试验前30分钟给予CGP44532、CGP56433A和BHF177。GABA受体激活(CGP44532和BHF177)和阻断(CGP56433A)都提高了所有组的ICSS阈值，导致尼古丁治疗组的尼古丁戒断效应加剧。GABA受体的激活和阻断对尼古丁戒断的非享乐性抑郁样方面的这些相似效果令人惊讶，可能反映了这些化合物在突触前异型和自体受体以及突触后GABA受体上的不同功效。
Nicotine dependence is maintained by the aversive, depression-like effects of nicotine withdrawal and the rewarding effects of acute nicotine. GABABreceptor antagonists exhibit antidepressant-like effects in rodents, whereas GABABreceptor agonists attenuate the rewarding effects of nicotine. Recent studies with GABABreceptor positive modulators showed that these compounds represent potentially improved medications for the treatment of nicotine dependence because of fewer side-effects than GABABreceptor agonists. Thus, GABABreceptor agonists and antagonists, and GABABreceptor positive modulators may have efficacy as smoking cessation aids by targeting different aspects of nicotine dependence and withdrawal. The present study assessed the effects of the GABABreceptor agonist CGP44532, the GABABreceptor antagonist CGP56433A, and the GABABreceptor positive modulator BHF177 on the anhedonic aspects of nicotine withdrawal. Rats were prepared with stimulating electrodes in the posterior lateral hypothalamus. After establishing stable intracranial self-stimulation (ICSS) thresholds, rats were prepared with subcutaneous osmotic minipumps delivering either nicotine or saline for 7 or 14days. ICSS thresholds were assessed 6h post-pump removal. Thirty hours after pump removal, CGP44532, CGP56433A, and BHF177 were administered 30min prior to ICSS testing. Both GABABreceptor activation (CGP44532 and BHF177) and blockade (CGP56433A) elevated ICSS thresholds in all groups, resulting in exacerbated effects of nicotine withdrawal in the nicotine-treated groups. These similar effects of GABABreceptor activation and blockade on the anhedonic depression-like aspects of nicotine withdrawal were surprising and perhaps reflect differential efficacy of these compounds at presynaptic hetero- and autoreceptors, as well as postsynaptic, GABABreceptors.