Deletion of α5 nicotine receptor subunits abolishes nicotinic aversive motivational effects in a manner that phenocopies dopamine receptor antagonism.
Deletion of α5 nicotine receptor subunits abolishes nicotinic aversive motivational effects in a manner that phenocopies dopamine receptor antagonism.
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DOI：
10.1111/ejn.13605
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
van der Kooy D
中科院分区：
文献类型：
--
作者：
Grieder TE;George O;Yee M;Bergamini MA;Chwalek M;Maal-Bared G;Vargas-Perez H;van der Kooy D
尼古丁成瘾是一种全球性的流行病，每年夺去数百万人的生命。α5烟碱乙酰胆碱受体（nAChR）亚基的基因缺失与尼古丁摄入量增加有关，然而，目前尚不清楚急性尼古丁是否更少厌恶或更有益，以及缺乏α5 nAChR亚基的小鼠是否会从慢性尼古丁中戒断。我们使用位置条件反射和条件性味觉回避范式来研究含有α5亚基的nAChR缺失（α5 −/−）对非依赖和尼古丁依赖和戒断小鼠的条件性接近和回避行为的影响，并将这些动机效应与多巴胺受体拮抗剂后引起的动机效应进行比较。我们发现，非依赖性α5 −/−小鼠发现低剂量、非激励性剂量的尼古丁会产生奖励，并且对较高厌恶剂量的尼古丁没有表现出厌恶性条件反应或味觉回避。此外，尼古丁依赖性α5 −/−小鼠对慢性尼古丁戒断没有表现出条件性厌恶动机反应，尽管它们继续表现出躯体戒断综合征。这些效应与多巴胺受体拮抗剂后观察到的效应表型相似，但不具有相加性，表明α5 nAChR亚基与多巴胺在相同的途径中起作用，并且对于在非依赖性和尼古丁依赖性和戒断性动机状态下尼古丁的厌恶性而非奖励性动机效应的体验至关重要。α5 nAChR亚基的基因缺失导致行为表型与拮抗多巴胺受体后观察到的表型完全匹配，因此，我们认为，含有α5亚基的烟碱受体的调节可能会改变多巴胺能信号传导，提示戒烟的新治疗方法。
Nicotine addiction is a worldwide epidemic that claims millions of lives each year. Genetic deletion of α5 nicotinic acetylcholine receptor (nAChR) subunits has been associated with increased nicotine intake, however, it remains unclear whether acute nicotine is less aversive or more rewarding, and whether mice lacking the α5 nAChR subunit can experience withdrawal from chronic nicotine. We used place conditioning and conditioned taste avoidance paradigms to examine the effect of α5 subunit-containing nAChR deletion (α5 −/−) on conditioned approach and avoidance behaviour in nondependent and nicotine-dependent and -withdrawn mice, and compared these motivational effects with those elicited after dopamine receptor antagonism. We show that nondependent α5 −/− mice find low, non-motivational doses of nicotine rewarding, and do not show an aversive conditioned response or taste avoidance to higher aversive doses of nicotine. Furthermore, nicotine-dependent α5 −/− mice do not show a conditioned aversive motivational response to withdrawal from chronic nicotine, although they continue to exhibit a somatic withdrawal syndrome. These effects phenocopy those observed after dopamine receptor antagonism, but are not additive, suggesting that α5 nAChR subunits act in the same pathway as dopamine and are critical for the experience of nicotine’s aversive, but not rewarding motivational effects in both a nondependent and nicotine-dependent and -withdrawn motivational state. Genetic deletion of α5 nAChR subunits leads to a behavioural phenotype that exactly matches that observed after antagonizing dopamine receptors, thus we suggest that modulation of nicotinic receptors containing α5 subunits may modify dopaminergic signalling, suggesting novel therapeutic treatments for smoking cessation.
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DOI：
10.1124/jpet.107.132977
发表时间：
2008-04-01
影响因子：
3.5
作者：
Jackson, K. J.;Martin, B. R.;Damaj, M. I.
通讯作者：
Damaj, M. I.
影响因子：
3.7
作者：
Chatterjee S;Santos N;Holgate J;Haass-Koffler CL;Hopf FW;Kharazia V;Lester H;Bonci A;Bartlett SE
通讯作者：
Bartlett SE
影响因子：
64.8
作者：
Picciotto, MR;Zoli, M;Changeux, JP
通讯作者：
Changeux, JP
影响因子：
25
作者：
Grieder, Taryn E.;Herman, Melissa A.;Contet, Candice;Tan, Laura A.;Vargas-Perez, Hector;Cohen, Ami;Chwalek, Michal;Maal-Bared, Geith;Freiling, John;Schlosburg, Joel E.;Clarke, Laura;Crawford, Elena;Koebel, Pascale;Repunte-Canonigo, Vez;Sanna, Pietro P.;Tapper, Andrew R.;Roberto, Marisa;Kieffer, Brigitte L.;Sawchenko, Paul E.;Koob, George F.;van der Kooy, Derek;George, Olivier
通讯作者：
George, Olivier
DOI：
10.1002/neu.10153
发表时间：
2002-12-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
Le Novère, N;Corringer, PJ;Changeux, JP
通讯作者：
Changeux, JP