Dissociation of the Effects of MTEP [3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on Conditioned Reinstatement and Reinforcement: Comparison between Cocaine and a Conventional Reinforcer
Dissociation of the Effects of MTEP [3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on Conditioned Reinstatement and Reinforcement: Comparison between Cocaine and a Conventional Reinforcer
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DOI：
10.1124/jpet.109.151357
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发表时间：
2009-06-01
影响因子：
3.5
通讯作者：
Weiss, F.
中科院分区：
文献类型：
--
作者：
Martin-Fardon, R.;Baptista, M. A. S.;Weiss, F.
为了加深对代谢型谷氨酸受体 (mGluR) 5 作为可卡因成瘾治疗靶点的潜力的了解，研究了 MTEP [3-[(2-甲基-1,3-噻唑-4-基)乙炔基]哌啶]（一种选择性 mGluR5 拮抗剂）对条件性恢复可卡因寻求的影响。为了测试 MTEP 对条件恢复的修改是否对药物导向行为具有选择性，或者反映了对动机行为的一般作用，还评估了 MTEP 对可口的常规奖励、甜炼乳 (SCM) 条件刺激诱导的恢复的影响。先前的数据表明，与可卡因自我给药相比，mGluR 操作优先干扰条件恢复。因此，使用用于建立条件恢复的相同可卡因剂量和 SCM 浓度，将 MTEP 对可卡因自我给药的影响与 MTEP 对 SCM 强化行为的影响进行比较。雄性 Wistar 大鼠经过训练，将辨别刺激 (S-D) 与可卡因或 SCM 的反应相关可用性联系起来，并在可卡因或 SCM 强化行为消失后接受恢复测试。 MTEP (0.3-10 mg/kg i.p.) 剂量依赖性地减弱可卡因 S-D 和 SCM S-D 的反应恢复作用。 MTEP 还减少了可卡因的自我给药，但没有明确的分级剂量反应曲线，并且没有改变 SCM 强化的反应。研究结果表明，食欲行为中 mGluR5 调节的谷氨酸传递受奖励相关刺激控制，但对可卡因寻求没有选择性。然而，数据表明，与传统奖励相比，mGluR5 在可卡因的急性强化作用中发挥着不同的作用。这些观察结果表明，mGluR5 是预防可卡因复吸的潜在治疗靶点，尽管 mGluR5 拮抗剂的作用概况仍有待更仔细地研究潜在的快感缺失效应。
To advance understanding of the potential of metabotropic glutamate receptor (mGluR) 5 as treatment targets for cocaine addiction, the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] piperidine] (a selective mGluR5 antagonist) on conditioned reinstatement of cocaine seeking were examined. To test whether modification of conditioned reinstatement by MTEP is selective for drug-directed behavior or reflects general actions on motivated behavior, effects of MTEP on reinstatement induced by a stimulus conditioned to palatable conventional reward, sweetened condensed milk (SCM), were also evaluated. Previous data suggest that mGluR manipulations preferentially interfere with conditioned reinstatement compared with cocaine self-administration. Therefore, the effects of MTEP on cocaine self-administration were compared with MTEP's effects on SCM-reinforced behavior using the same cocaine doses and SCM concentrations employed for establishing conditioned reinstatement. Male Wistar rats were trained to associate a discriminative stimulus (S-D) with response-contingent availability of cocaine or SCM and subjected to reinstatement tests after extinction of cocaine or SCM-reinforced behavior. MTEP (0.3-10 mg/kg i.p.) dose-dependently attenuated the response-reinstating effects of both the cocaine S-D and SCM S-D. MTEP also decreased cocaine self-administration without a clear graded dose-response profile and did not modify SCM-reinforced responding. The findings implicate mGluR5-regulated glutamate transmission in appetitive behavior controlled by reward-related stimuli but without selectivity for cocaine seeking. However, the data suggest a differential role for mGluR5 in the acute reinforcing effects of cocaine versus conventional reward. These observations identify mGluR5 as potential treatment targets for cocaine relapse prevention, although the profile of action of mGluR5 antagonists remains to be more closely examined for potential anhedonic effects.