Department of Psychiatry, School of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603, USA.
Psychopharmacology (Berl). 2012 May;221(2):317-27. doi: 10.1007/s00213-011-2578-8. Epub 2011 Dec 3.
The involvement of metabotropic glutamate 5 (mGlu5) receptors has been suggested in the reinforcing effects of psychostimulants. However, little is known about the role of these receptors in psychostimulant withdrawal.
The role of mGlu5 receptors was assessed in the anhedonic and somatic aspects of psychostimulant withdrawal.
Anhedonia was assessed with the discrete-trial current-intensity intracranial self-stimulation (ICSS) procedure after the termination of cocaine (180 mg kg(-1) day(-1), salt, 3 days, i.p.) or nicotine (40 mg kg(-1) day(-1), base, 28 days, s.c.) administration via osmotic minipumps in mGlu5 receptor knockout (mGluR5(-/-)) and wild-type (mGluR5(+/+)) mice. Somatic signs were assessed during nicotine withdrawal. The effects of the nicotinic acetylcholine receptor antagonist mecamylamine on ICSS thresholds were assessed during chronic nicotine administration.
Nicotine-treated mGluR5(+/+) and mGluR5(-/-) mice demonstrated similar threshold elevations during mecamylamine-precipitated withdrawal compared with their saline-treated counterparts. During spontaneous nicotine and cocaine withdrawal, thresholds in drug-withdrawing mGluR5(+/+), but not mGluR5(-/-), mice were elevated up to 72 h of nicotine/cocaine withdrawal and then returned to baseline, indicating attenuation of withdrawal-induced anhedonia in mGluR5(-/-) mice. Nicotine-withdrawing mGluR5(+/+), but not mGluR5(-/-), mice showed increases in somatic signs compared with saline-treated counterparts.
mGlu5 receptor null mutation attenuates the anhedonic and somatic effects of psychostimulant withdrawal. This attenuated withdrawal in mGluR5(-/-) mice may result from the lack of drug-induced adaptations in mGlu5 receptor function that may occur in mGluR5(+/+) mice with chronic drug administration. Thus, these results suggest the involvement of mGlu5 receptors in psychostimulant dependence and the mediation of the anhedonic and somatic signs of psychostimulant withdrawal.
代谢型谷氨酸 5 型受体（mGlu5）的参与已被认为与精神兴奋剂的强化效应有关。然而，关于这些受体在精神兴奋剂戒断中的作用知之甚少。
评估 mGlu5 受体在精神兴奋剂戒断时快感缺失和躯体症状中的作用。
通过在经渗透微型泵给予可卡因（180mg/kg/天，盐，3 天，腹腔内注射）或尼古丁（40mg/kg/天，碱，28 天，皮下注射）后，使用离散试验电流强度颅内自我刺激（ICSS）程序评估快感缺失，在 mGlu5 受体敲除（mGluR5(-/-)）和野生型（mGluR5(+/+)）小鼠中评估精神兴奋剂戒断时的躯体症状。在慢性尼古丁给药期间，评估烟碱型乙酰胆碱受体拮抗剂美加明对 ICSS 阈值的影响。
与生理盐水处理的对照组相比，尼古丁处理的 mGluR5(+/+)和 mGluR5(-/-)小鼠在美加明诱发的戒断期间表现出相似的阈值升高。在自发的尼古丁和可卡因戒断期间，在药物戒断的 mGluR5(+/+)小鼠中，但不在 mGluR5(-/-)小鼠中，阈值升高持续到尼古丁/可卡因戒断 72 小时，然后恢复到基线，表明 mGluR5(-/-)小鼠中戒断引起的快感缺失减弱。与生理盐水处理的对照组相比，尼古丁戒断的 mGluR5(+/+)小鼠表现出更多的躯体症状。
mGlu5 受体缺失突变减弱了精神兴奋剂戒断时的快感缺失和躯体症状。mGluR5(-/-)小鼠中这种减弱的戒断可能是由于缺乏药物诱导的 mGlu5 受体功能适应，而在慢性药物给药的 mGluR5(+/+)小鼠中可能发生这种适应。因此，这些结果表明 mGlu5 受体参与了精神兴奋剂依赖，并介导了精神兴奋剂戒断时的快感缺失和躯体症状。
