Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Biol Psychiatry. 2010 May 1;67(9):812-22. doi: 10.1016/j.biopsych.2009.09.016. Epub 2009 Nov 7.
Systemic modulation of Group I and II metabotropic glutamate receptors (mGluRs) regulate ethanol self-administration in a variety of animal models. Although these receptors are expressed in reward-related brain regions, the anatomical specificity of their functional involvement in ethanol self-administration remains to be characterized. This study sought to evaluate the functional role of Group I (mGluR5) and Group II (mGluR2/3) in mesocorticolimbic brain regions in ethanol self-administration.
Alcohol-preferring (P) rats, a genetic model of high alcohol drinking, were trained to self-administer ethanol (15% v/v) versus water in operant conditioning chambers. Effects of brain site-specific infusion of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and the mGluR2/3 agonist were then assessed on the maintenance of self-administration.
Microinjection of the mGluR5 antagonist MPEP in the nucleus accumbens reduced ethanol self-administration at a dose that did not alter locomotor activity. By contrast, infusion of the mGluR2/3 agonist LY379268 in the nucleus accumbens reduced self-administration and produced nonspecific reductions in locomotor activity. The mGluR5 involvement showed anatomical specificity as evidenced by lack of effect of MPEP infusion in the dorsomedial caudate or medial prefrontal cortex on ethanol self-administration. To determine reinforcer specificity, P-rats were trained to self-administer sucrose (.4% w/v) versus water, and effects of intra-accumbens MPEP were tested. The MPEP did not alter sucrose self-administration or motor behavior.
These results suggest that mGluR5 activity specifically in the nucleus accumbens is required for the maintenance of ethanol self-administration in individuals with genetic risk for high alcohol consumption.
I 型和 II 型代谢型谷氨酸受体（mGluRs）的全身调节可调节多种动物模型中的乙醇自我给药。尽管这些受体在与奖励相关的脑区表达，但它们在乙醇自我给药中的功能参与的解剖学特异性仍有待描述。本研究旨在评估中脑皮质边缘脑区中 I 组（mGluR5）和 II 组（mGluR2/3）在乙醇自我给药中的功能作用。
酒精偏好（P）大鼠是一种高饮酒的遗传模型，在操作性条件反射室中接受乙醇（15%v/v）与水的自我给药训练。然后评估脑区特异性注射 mGluR5 拮抗剂 2-甲基-6-（苯乙炔基）吡啶盐酸盐（MPEP）和 mGluR2/3 激动剂对自我给药的维持作用。
在伏隔核中注射 mGluR5 拮抗剂 MPEP 可降低乙醇自我给药的剂量，而不改变运动活动。相比之下，在伏隔核中注射 mGluR2/3 激动剂 LY379268 可降低自我给药，并产生非特异性的运动活动减少。mGluR5 的参与表现出解剖学特异性，因为 MPEP 输注在背侧尾状核或内侧前额叶皮质中对乙醇自我给药没有影响。为了确定强化物特异性，P 大鼠接受了自我给予蔗糖（0.4%w/v）与水的训练，并测试了伏隔核内 MPEP 的作用。MPEP 并未改变蔗糖自我给药或运动行为。
这些结果表明，具有高饮酒遗传风险的个体中，伏隔核中 mGluR5 的活性是维持乙醇自我给药所必需的。
