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亲代谢型谷氨酸2/3受体激动剂LY404039可减少嗜酒(P)大鼠的觅酒行为,但不影响其酒精自服行为。

The metabotropic glutamate 2/3 receptor agonist LY404039 reduces alcohol-seeking but not alcohol self-administration in alcohol-preferring (P) rats.

作者信息

Rodd Zachary A, McKinzie David L, Bell Richard L, McQueen Victoria K, Murphy James M, Schoepp Darryle D, McBride William J

机构信息

Department of Psychiatry, Indiana University School of Medicine, Institute of Psychiatric Research, Indianapolis, 46202-4887, USA.

出版信息

Behav Brain Res. 2006 Aug 10;171(2):207-15. doi: 10.1016/j.bbr.2006.03.032. Epub 2006 May 6.

Abstract

Metabotropic glutamate (mGlu) receptors have been shown to mediate a number of behaviors including emotionality and responsivity to stress as demonstrated by efficacy in preclinical and clinical studies. The objective of this study was to assess the effects of the mGlu2/3 receptor agonist LY404039 (LY) on operant ethanol (EtOH) self-administration during alcohol seeking (pavlovian spontaneous recovery, PSR), alcohol relapse (alcohol deprivation effect, ADE), and maintenance responding for alcohol. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5-fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1h sessions. After at least 10 weeks of daily 1 h sessions, rats underwent seven extinction sessions, followed by 2 weeks of no manipulation, and then rats were tested for the expression of an EtOH PSR for four sessions. Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (alcohol relapse). Finally, the effects of LY upon maintenance EtOH and water responding were assessed once stable responding was reestablished. The mGlu2/3 receptor agonist LY404039 reduced responding on the EtOH in the PSR test. LY also reduced the expression of an alcohol deprivation effect (ADE) during relapse, but did not reduce EtOH responding under maintenance conditions. The results of this study demonstrate that activating mGlu2/3 receptors inhibits the expression of alcohol seeking and relapse behavior without altering alcohol self-administration behavior.

摘要

代谢型谷氨酸(mGlu)受体已被证明可介导多种行为,包括情绪和对应激的反应性,临床前和临床研究中的有效性已证实了这一点。本研究的目的是评估mGlu2/3受体激动剂LY404039(LY)对觅酒期间(巴甫洛夫式自发恢复,PSR)、酒精复发(酒精剥夺效应,ADE)以及酒精维持反应中的操作性乙醇(EtOH)自我给药的影响。成年嗜酒(P)大鼠在双杠杆操作性条件反射箱中接受训练,以在每日1小时的训练中,按照固定比率5-固定比率1(FR5-FR1)的强化程序同时自我给药15%乙醇(v/v)和水。在每天1小时的训练至少持续10周后,大鼠接受7次消退训练,随后2周不进行任何操作,然后对大鼠进行4次测试以评估乙醇PSR的表达。然后,大鼠在其饲养笼中饲养一周,之后再返回操作性条件反射箱,可获取乙醇和水(酒精复发)。最后,一旦重新建立稳定反应,就评估LY对维持乙醇和水反应的影响。mGlu2/3受体激动剂LY404039在PSR测试中减少了对乙醇的反应。LY还减少了复发期间酒精剥夺效应(ADE)的表达,但在维持条件下并未减少对乙醇的反应。本研究结果表明,激活mGlu2/3受体可抑制觅酒和复发行为的表达,而不会改变酒精自我给药行为。

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