Reduced cocaine self-administration in muscarinic M5 acetylcholine receptor-deficient mice
Reduced cocaine self-administration in muscarinic M5 acetylcholine receptor-deficient mice
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DOI：
10.1523/jneurosci.2077-05.2005
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发表时间：
2005-09-07
影响因子：
5.3
通讯作者：
Caine, SB
中科院分区：
文献类型：
--
作者：
Thomsen, M;Woldbye, DPD;Caine, SB
可卡因的强化作用与腹侧纹状体细胞外多巴胺浓度的增加有关。几项研究表明，M-5毒蕈碱受体促进纹状体多巴胺的释放。我们测试了这一假设，即可卡因的增强作用减少M-5受体缺陷小鼠使用长期静脉注射可卡因自我管理广泛回交小鼠。我们还评估了是否操作性能一般，而不是可卡因自我管理具体，在突变小鼠改变。为此，我们评估了食物维持的操作行为和可卡因自我管理下的固定比例1和渐进的比例（PR）的强化时间表。我们还评估了使用几个剂量的可卡因在实验幼稚小鼠中获得自我给药。M5受体缺失减少了PR强化时间表下低至中等剂量可卡因的自我给药，并减少了实验幼稚小鼠中低剂量自我给药的获得。我们没有发现基因型之间的食物维持行为的差异。本研究扩展了我们以前的研究结果，使用回交小鼠和覆盖各种实验条件。我们的研究结果表明，M5受体缺失减少了低剂量可卡因的增强作用，并确定了可能观察到这种情况的特定条件。
The reinforcing effects of cocaine have been related to increased extracellular concentrations of dopamine in the ventral striatum. Several studies suggest that M-5 muscarinic receptors facilitate striatal dopamine release. We tested the hypothesis that the reinforcing effects of cocaine are decreased in M-5 receptor-deficient mice using chronic intravenous cocaine self-administration in extensively backcrossed mice. We also assessed whether operant performance generally, rather than cocaine self-administration specifically, was altered in the mutant mice. To this end, we evaluated both food-maintained operant behavior and cocaine self-administration under a fixed ratio 1 and a progressive ratio (PR) schedule of reinforcement. We also evaluated acquisition of self-administration in experimentally naive mice using several doses of cocaine. M5 receptor deletion decreased self-administration of low to moderate doses of cocaine under a PR schedule of reinforcement and diminished acquisition of self-administration of a low dose in experimentally naive mice. We found no differences between genotypes in food-maintained behavior. The present study extends our previous findings using backcrossed mice and covering various experimental conditions. Our results indicate that M5 receptor deletion diminished the reinforcing effects of low doses of cocaine and identified specific conditions under which this may be observed.