MPEP Lowers Binge Drinking in Male and Female C57BL/6 Mice: Relationship with mGlu5/Homer2/Erk2 Signaling

Background 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. Methods 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. Results 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. Conclusions 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. MPEP reduced alcohol consumption during drinking in the dark (DID) in male and female C57BL/6 mice (Fig A) without changes in Homer2/Erk2 expression. Locomotor activity did not mediate effects of MPEP on alcohol intake, but it did correlate with alcohol intake. Alcohol intake during DID predicted bed nucleus of the stria terminalis (BNST) Homer2 expression. Our data provide support for a role for metabotropic glutama