Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China.
Alcohol Clin Exp Res. 2021 Apr;45(4):732-742. doi: 10.1111/acer.14576. Epub 2021 Mar 28.
Metabotropic glutamate receptor 5 (mGlu5) plays an important role in excessive alcohol use and the mGlu5/Homer2/Erk2 signaling pathway has been implicated in binge drinking. The mGlu5 negative allosteric modulator (NAM) 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) has been shown to reduce binge drinking in male mice, but less is known about its effect on female mice. Here, we sought to determine whether sex differences exists in the effects of MPEP on binge drinking and whether they relate to changes in the MPEP mGlu5/Homer2/Erk2 signaling.
We measured the dose-response effect of MPEP on alcohol consumption in male and female mice using the Drinking in the Dark (DID) paradigm to assess potential sex differences. To rule out possible confounds of MPEP on locomotion, we measured the effects of MPEP on locomotor activity and drinking simultaneously during DID. Lastly, to test whether MPEP-induced changes in alcohol consumption were related to changes in Homer2 or Erk2 expression, we performed qPCR using brain tissue acquired from mice that had undergone 7 days of DID.
30 mg/kg MPEP reduced binge alcohol consumption across female and male mice, with no sex differences in the dose-response relationship. Locomotor activity did not mediate the effects of MPEP on alcohol intake, but activity correlated with alcohol intake independent of MPEP. MPEP did not change the expression of Homer2 and Erk2 mRNA in the bed nucleus of the stria terminalis (BNST) or nucleus accumbens in mice whose drinking was reduced by MPEP, relative to saline. There was a positive relationship between alcohol intake and Homer2 expression in the BNST.
MPEP reduced alcohol consumption during DID in male and female C57BL/6 mice but did not change Homer2/Erk2 expression. Locomotor activity did not mediate the effects of MPEP on alcohol intake, though it correlated with alcohol intake. Alcohol intake during DID predicted BNST Homer2 expression. These data provide support for the regulation of alcohol consumption by mGlu5 across sexes.
代谢型谷氨酸受体 5（mGlu5）在过度饮酒中发挥重要作用，mGlu5/Homer2/Erk2 信号通路与 binge drinking 有关。mGlu5 负变构调节剂（NAM）2-甲基-6-（苯乙炔基）吡啶盐酸盐（MPEP）已被证明可减少雄性小鼠的 binge drinking，但对雌性小鼠的影响知之甚少。在这里，我们试图确定 MPEP 对 binge drinking 的影响是否存在性别差异，以及这些差异是否与 MPEP mGlu5/Homer2/Erk2 信号的变化有关。
我们使用暗饮（DID）范式测量 MPEP 对雄性和雌性小鼠饮酒量的剂量反应效应，以评估潜在的性别差异。为了排除 MPEP 对运动活动的可能干扰，我们在 DID 期间同时测量 MPEP 对运动活动和饮酒的影响。最后，为了测试 MPEP 诱导的饮酒量变化是否与 Homer2 或 Erk2 表达的变化有关，我们使用经过 7 天 DID 的小鼠的脑组织进行了 qPCR。
30mg/kg 的 MPEP 减少了雌雄小鼠的 binge 饮酒量，剂量反应关系无性别差异。运动活动并没有介导 MPEP 对酒精摄入的影响，但活动与酒精摄入相关，与 MPEP 无关。MPEP 未改变减少 MPEP 饮酒的小鼠中终纹床核（BNST）或伏隔核中 Homer2 和 Erk2 mRNA 的表达，与生理盐水相比。BNST 中酒精摄入量与 Homer2 表达呈正相关。
MPEP 减少了 C57BL/6 雄性和雌性小鼠 DID 期间的饮酒量，但未改变 Homer2/Erk2 表达。运动活动并没有介导 MPEP 对酒精摄入的影响，但与酒精摄入相关。DID 期间的饮酒量预测了 BNST Homer2 的表达。这些数据为 mGlu5 在不同性别中调节酒精摄入提供了支持。
