Sex-dependent Schizophrenia and Drug Reward Behavioral Phenotypes in Metabotropic Glutamate 5 Receptor Heterozygous and Homozygous Mice

Background and Hypothesis The metabotropic glutamate 5 (mGlu5) receptor is a potential therapeutic target for psychiatric disorders, including schizophrenia and substance use disorders. Indeed, mGlu5 is expressed in forebrain regions (eg, striatum, prefrontal cortex), and mGlu5 modulates N-methyl-D-aspartate receptor function and second messenger signaling. Also, male mice lacking mGlu5 display schizophrenia-like and substance use-relevant behaviors. However, there are limited investigations of sex differences or gene-dose effects in this model.Study Designs We evaluated schizophrenia-relevant and cocaine reward-relevant behaviors in adult male and female mice with heterozygous (mGlu5 HET) and homozygous (mGlu5 HOMO) mGlu5 deletion and their wildtype-like (WT) littermates. We assessed locomotion and exploration, anxiety, sensorimotor gating, novel object recognition, fear conditioning, social interaction, cocaine sensitization, and cocaine-conditioned place preference. We also examined fear memory generalization.Study Results mGlu5 HOMO mice of both sexes showed hyperlocomotion and anxiolytic-like behavior in the open field, as well as enhanced cocaine sensitization and persistent cocaine place preference. When tested for memory generalization, mGlu5 HOMO mice exhibited greater freezing to a novel context, suggesting overgeneralization of fear in these mice. mGlu5 HOMO females showed reduced sensorimotor gating. mGlu5 HET mice of both sexes showed a largely similar phenotype to sex-matched WT controls.Conclusions Our data demonstrate schizophrenia- and drug use-relevant phenotypes in mGlu5 HOMO mice, some of which are sex-dependent. These phenotypes do not occur in mGlu5 HET males and females. We also show for the first time an overgeneralization phenotype in mGlu5 HOMO mice, which may be related to poor contextual discrimination.