Thus, additional research into the anxiolytic potential of mGlu5 antagonists, and the potential mechanisms through which these anxiolytic effects arise (e.g., direct receptor-mediated changes in excitatory or inhibitory neurotransmission and/or alternations in cannabinoid receptor 1-dependent long-term depression; including sex differences in antagonist responsiveness), could provide beneficial clinical tools for the treatment of both substance abuse and comorbid anxiety-related disorders. Here, GRM5 is linked to substance abuse.