Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice.
Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout mice.
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DOI：
10.1007/s00213-011-2225-4
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发表时间：
2011-08
影响因子：
3.4
通讯作者：
Fink-Jensen, Anders
中科院分区：
文献类型：
--
作者：
Schmidt, Lene S.;Thomsen, Morgane;Weikop, Pia;Dencker, Ditte;Wess, Juergen;Woldbye, David P. D.;Wortwein, Gitta;Fink-Jensen, Anders
可卡因的强化作用是由中脑边缘多巴胺系统介导的。行为学和神经化学研究表明，胆碱能毒蕈碱M4受体亚型在调节多巴胺能神经传递中起重要作用。在这里，我们首次研究了M4受体参与可卡因的强化作用，使用长期静脉注射可卡因自我管理广泛回交M4受体敲除（M4−/−）小鼠。我们评估了在实验幼稚小鼠中可卡因自我给药的获得。可卡因自我管理和食物维持的操作性行为进行了评估下固定的比例1（FR 1）和渐进的比例（PR）的时间表的强化。此外，可卡因诱导的多巴胺释放和可卡因诱导的多动症进行了评价。在FR 1和PR强化方案下，M4−/−小鼠在中等剂量可卡因下比其野生型同窝小鼠（M4+/+）获得了显著更多的可卡因代谢物，并达到了更高的临界点。在PR方案下，M4−/−小鼠在最低液体食物浓度下表现出显著更高的反应率。根据这些结果，与M4+/+小鼠相比，M4−/−小鼠中可卡因诱导的丘脑核多巴胺流出和过度运动增加。我们的数据表明，M4受体在奖赏回路的调节中起重要作用，并可能作为药物成瘾治疗的新靶点。
The reinforcing effects of cocaine are mediated by the mesolimbic dopamine system. Behavioral and neurochemical studies have shown that the cholinergic muscarinic M4 receptor subtype plays an important role in regulation of dopaminergic neurotransmission. Here we investigated for the first time the involvement of M4 receptors in the reinforcing effects of cocaine using chronic intravenous cocaine self-administration in extensively backcrossed M4 receptor knockout (M4−/−) mice. We evaluated acquisition of cocaine self-administration in experimentally naïve mice. Both cocaine self-administration and food-maintained operant behavior were evaluated under fixed ratio 1 (FR 1) and progressive ratio (PR) schedules of reinforcement. In addition, cocaine-induced dopamine release and cocaine-induced hyperactivity was evaluated. M4−/− mice earned significantly more cocaine reinforcers and reached higher breaking points than their wildtype littermates (M4+/+) at intermediate doses of cocaine under both FR 1 and PR schedules of reinforcement. Under the PR schedule, M4−/− mice exhibited significantly higher response rates at the lowest liquid food concentration. In accordance with these results, cocaine-induced dopamine efflux in the nucleus accumbens and hyperlocomotion were increased in M4−/− mice compared to M4+/+ mice. Our data suggest that M4 receptors play an important role in regulation of the reward circuitry and may serve as a new target in the medical treatment of drug addiction.
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DOI：
10.1124/jpet.104.082537
发表时间：
2005-05-01
影响因子：
3.5
作者：
Chen, SR;Wess, J;Pan, HL
通讯作者：
Pan, HL
影响因子：
3.4
作者：
Caine, SB;Negus, SS;Mello, NK
通讯作者：
Mello, NK
一种 M4 mAChR 的异位增效剂可调节海马突触传递
影响因子：
14.8
作者：
Shirey, Jana K.;Xiang, Zixiu;Conn, P. Jeffrey
通讯作者：
Conn, P. Jeffrey
影响因子：
64.8
作者：
Rocha, BA;Scearce-Levie, K;Hen, R
通讯作者：
Hen, R
影响因子：
15.9
作者：
Gerlai, R
通讯作者：
Gerlai, R