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首页> 外文期刊>Addiction biology >A novel mGluR5 antagonist, MFZ 10-7, inhibits cocaine-taking and cocaine-seeking behavior in rats
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A novel mGluR5 antagonist, MFZ 10-7, inhibits cocaine-taking and cocaine-seeking behavior in rats

机译：新型mGluR5拮抗剂MFZ 10-7抑制大鼠的可卡因吸收和可卡因寻找行为

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摘要

Pre-clinical studies suggest that negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5), including 2-methyl-6-(phenylethynyl)pyridine (MPEP), 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]pyridine (MTEP) and fenobam are highly effective in attenuating drug-taking and drug-seeking behaviors. However, both MPEP and MTEP have no translational potential for use in humans because of their off-target effects and short half-lives. Here, we report that 3-fluoro-5-[(6-methylpyridin-2-yl) ethynyl]benzonitrile (MFZ 10-7), a novel mGluR5 NAM, is more potent and selective than MPEP, MTEP and fenobam in both in vitro binding and functional assays. Similar to MTEP, intraperitoneal administration of MFZ 10-7 inhibited intravenous cocaine self-administration, cocaine-induced reinstatement of drug-seeking behavior and cocaine-associated cue-induced cocaine-seeking behavior in rats. Although MFZ 10-7 and MTEP lowered the rate of oral sucrose self-administration, they did not alter total sucrose intake. Further, MFZ 10-7 appeared to be more potent than MTEP in inducing downward shifts in the cocaine dose-response curve, but less effective than MTEP in attenuating sucrose-induced reinstatement of sucrose-seeking behavior. MFZ 10-7 and MTEP had no effect on basal locomotor behavior. These findings not only provide additional evidence supporting an important role for mGluR5 in cocaine reward and addiction, but also introduce a new tool for both in vitro and in vivo investigations with which to further characterize this role.
机译：临床前研究表明，代谢型谷氨酸受体亚型5（mGluR5）的负变构调节剂（NAM），包括2-甲基-6-（苯基乙炔基）吡啶（MPEP），3-[（2-甲基-1,3-噻唑-4-基）乙炔基]吡啶（MTEP）和芬诺班在减轻药物吸收和寻求药物的行为方面非常有效。但是，由于MPEP和MTEP具有脱靶作用和半衰期短，因此它们在人类中都没有翻译潜力。在这里，我们报道了一种新型的mGluR5 NAM 3-氟-5-[（6-甲基吡啶-2-基）乙炔基]苄腈（MFZ 10-7）比MPEP，MTEP和fenobam更有效和更具选择性。体外结合和功能测定。与MTEP相似，腹腔注射MFZ 10-7可抑制大鼠的静脉内可卡因自我给药，可卡因诱导的药物寻求行为的恢复以及可卡因相关的提示诱导的可卡因寻求行为。尽管MFZ 10-7和MTEP降低了口服蔗糖的自我给药率，但它们并未改变总蔗糖摄入量。此外，MFZ 10-7似乎在诱导可卡因剂量反应曲线下移方面比MTEP更有效，但在减弱蔗糖诱导的蔗糖寻求行为恢复方面，其效果不如MTEP。 MFZ 10-7和MTEP对基础运动行为没有影响。这些发现不仅提供了支持mGluR5在可卡因奖励和成瘾中起重要作用的其他证据，而且为进一步表征这种作用的体外和体内研究引入了新工具。

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