Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia
Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia
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DOI：
10.1073/pnas.162371899
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发表时间：
2002-08-20
影响因子：
11.1
通讯作者：
Wess, J
中科院分区：
文献类型：
--
作者：
Basile, AS;Fedorova, I;Wess, J
M-5毒蕈碱受体是最后一个被克隆的毒蕈碱受体家族成员（M-1-M-5），其生理作用目前知之甚少。在脑中，M-5受体亚型优先由黑质和腹侧被盖区的多巴胺能神经元表达。已知位于腹侧被盖区的多巴胺能神经元在调节阿片类药物和其他滥用药物的奖赏效应以及阿片类药物/药物戒断症状的表现中起重要作用。因此，我们推测M-5受体的乙酰胆碱依赖性激活可能调节阿片奖励和戒断的表现。在一系列行为、生物化学和神经化学研究中，使用M-5受体缺陷小鼠（M-5（-/-）小鼠）作为新的实验工具，对这一假设进行了测试。我们发现，吗啡的奖励作用，在条件性位置偏爱范式中测量，在M-5（-/-）小鼠中显著降低。此外，在M-5（-/-）小鼠中，纳洛酮诱导的吗啡戒断症状的躯体和情感成分均显著减弱。与此相反，吗啡的镇痛效果和发展的耐受吗啡的镇痛效果仍然没有改变的缺乏M-5受体。M-5受体活性调节吗啡奖赏和戒断过程的发现表明，M-5受体可能是治疗阿片成瘾的新靶点。
Little is known about the physiological roles of the M-5 muscarinic receptor, the last member of the muscarinic receptor family (M-1-M-5) to be cloned. In the brain, the M-5 receptor subtype is preferentially expressed by dopaminergic neurons of the substantia nigra and the ventral tegmental area. Dopaminergic neurons located in the ventral tegmental area are known to play important roles in mediating both the rewarding effects of opiates and other drugs of abuse and the manifestations of opiate/drug withdrawal symptoms. We therefore speculated that acetylcholine-dependent activation of M-5 receptors might modulate the manifestations of opiate reward and withdrawal. This hypothesis was tested in a series of behavioral, biochemical, and neurochemical studies using M-5 receptor-deficient mice (M-5(-/-) mice) as novel experimental tools. We found that the rewarding effects of morphine, as measured in the conditioned place preference paradigm, were substantially reduced in M-5(-/-) mice. Furthermore, both the somatic and affective components of naloxone-induced morphine withdrawal symptoms were significantly attenuated in M-5(-/-) mice. In contrast, the analgesic efficacy of morphine and the development of tolerance to the analgesic effects of morphine remained unaltered by the lack of M-5 receptors. The finding that M-5 receptor activity modulates both morphine reward and withdrawal processes suggests that M-5 receptors may represent a novel target for the treatment of opiate addiction.