Basile Anthony S, Fedorova Irina, Zapata Agustin, Liu Xiaoguang, Shippenberg Toni, Duttaroy Alokesh, Yamada Masahisa, Wess Jurgen
Neuroscience Group, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11452-7. doi: 10.1073/pnas.162371899. Epub 2002 Aug 1.
Little is known about the physiological roles of the M5 muscarinic receptor, the last member of the muscarinic receptor family (M1-M5) to be cloned. In the brain, the M5 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 M5 receptors might modulate the manifestations of opiate reward and withdrawal. This hypothesis was tested in a series of behavioral, biochemical, and neurochemical studies using M5 receptor-deficient mice (M5-/- 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 M5-/- mice. Furthermore, both the somatic and affective components of naloxone-induced morphine withdrawal symptoms were significantly attenuated in M5-/- 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 M5 receptors. The finding that M5 receptor activity modulates both morphine reward and withdrawal processes suggests that M5 receptors may represent a novel target for the treatment of opiate addiction.
毒蕈碱受体家族（M1 - M5）中最后一个被克隆的成员——M5毒蕈碱受体的生理作用鲜为人知。在大脑中，M5受体亚型主要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介导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M5受体的乙酰胆碱依赖性激活可能调节阿片类奖赏和戒断的表现。我们使用M5受体缺陷小鼠（M5 - / - 小鼠）作为新的实验工具，通过一系列行为、生化和神经化学研究对这一假设进行了验证。我们发现，在条件性位置偏爱范式中测量的吗啡奖赏效应在M5 - / - 小鼠中大幅降低。此外，M5 - / - 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轻。相比之下，吗啡的镇痛效果以及对吗啡镇痛作用的耐受性发展并未因M5受体的缺失而改变。M5受体活性调节吗啡奖赏和戒断过程这一发现表明，M5受体可能是治疗阿片类成瘾的新靶点。
