在有乙醇依赖史的大鼠中，mGlu2/3 激动剂 LY379268 和 mGlu5 拮抗剂 MTEP 对乙醇觅药和强化的影响存在差异。
Effects of the mGlu2/3 agonist LY379268 and the mGlu5 antagonist MTEP on ethanol seeking and reinforcement are differentially altered in rats with a history of ethanol dependence.
机构信息
The Scripps Research Institute, Molecular and Integrative Neurosciences Department, La Jolla, California 92037, USA.
出版信息
Biol Psychiatry. 2010 May 1;67(9):804-11. doi: 10.1016/j.biopsych.2010.01.005. Epub 2010 Feb 26.
BACKGROUND
Growing evidence supports a role of metabotropic glutamate receptors (mGluRs) in ethanol reinforcement, ethanol seeking, and ethanol withdrawal. To extend the understanding of the role of mGluRs in the addiction-relevant effects of ethanol as well as of the treatment target potential of these receptors for alcohol abuse, the effects of a selective mGlu2/3 agonist (LY379268) and a selective mGlu5 antagonist (MTEP) were tested on two processes central to alcohol addiction: ethanol reinforcement and stress-induced reinstatement of ethanol seeking in rats with a history of ethanol dependence.
METHODS
Following operant ethanol self-administration training, male Wistar rats were made dependent by intragastric ethanol intubations. Ethanol dependence was confirmed by the presence of somatic withdrawal signs. Following 2 weeks of withdrawal, stable ethanol self-administration was reestablished, and the effects of LY379268 (0-3 mg/kg subcutaneous) and MTEP (0-3 mg/kg, intraperitoneal) on ethanol self-administration were determined in both nondependent and postdependent rats. A second set of rats underwent extinction training and then was tested for the effects of LY379268 or MTEP on reinstatement of ethanol seeking induced by footshock stress.
RESULTS
LY379268 and MTEP dose-dependently reduced both ethanol self-administration and reinstatement of ethanol seeking induced by footshock stress. Additionally, LY379268 was more effective than MTEP in inhibiting both behaviors in postdependent than in nondependent animals.
CONCLUSIONS
These findings suggest that neuroadaptation associated with chronic ethanol exposure or withdrawal alters the sensitivity of mGlu2/3 receptors, with implications for the understanding of the neural basis of alcohol dependence and the treatment target potential of these receptors.
背景
越来越多的证据表明代谢型谷氨酸受体（mGluRs）在乙醇强化、乙醇寻求和乙醇戒断中发挥作用。为了进一步了解 mGluRs 在与乙醇成瘾相关的作用以及这些受体作为酒精滥用治疗靶点的潜力，本研究测试了一种选择性 mGlu2/3 激动剂（LY379268）和一种选择性 mGlu5 拮抗剂（MTEP）对两种与酒精成瘾相关的核心过程的影响：乙醇强化和应激诱导的乙醇寻求复吸。
方法
在进行操作性乙醇自我给药训练后，雄性 Wistar 大鼠通过胃内乙醇插管形成依赖。通过出现躯体戒断症状来确认乙醇依赖。在戒断 2 周后，重新建立稳定的乙醇自我给药，在非依赖和依赖后大鼠中确定 LY379268（0-3mg/kg 皮下）和 MTEP（0-3mg/kg，腹腔内）对乙醇自我给药的影响。第二组大鼠接受了消退训练，然后测试 LY379268 或 MTEP 对电击应激诱导的乙醇寻求复吸的影响。
结果
LY379268 和 MTEP 剂量依赖性地降低了乙醇自我给药和电击应激诱导的乙醇寻求复吸。此外，与非依赖动物相比，LY379268 在抑制依赖后动物的这两种行为方面比 MTEP 更有效。
结论
这些发现表明，与慢性乙醇暴露或戒断相关的神经适应改变了 mGlu2/3 受体的敏感性，这对理解酒精依赖的神经基础和这些受体的治疗靶点潜力具有重要意义。
Zotero 插件