Investigating metabotropic glutamate receptors as molecular targets for next-generation pharmacotherapies for alcohol use disorder

INTRODUCTION: Alcohol use disorder (AUD) is a major public health concern with few available pharmacotherapy options. There remains a critical need to identify novel molecular targets for more effective treatments. Evidence suggests that AUD is associated with dysregulated glutamatergic neurotransmission, including a hyperglutamatergic state that contributes to the development and maintenance of alcohol seeking behaviors. AREAS COVERED: Recent advances in characterizing neuronal, glial, and synaptic changes underlying AUD pathophysiology have identified the metabotropic glutamate receptor 2 (mGluR2) as a promising therapeutic target. As a presynaptic glutamate autoreceptor, pharmacological activation of mGluR2 May help modulate altered glutamatergic signaling observed in AUD. This review summarizes preclinical evidence demonstrating that mGluR2 agonists and positive allosteric modulators can effectively reduce alcohol seeking behaviors. This review also discusses emerging evidence linking glutamatergic dysregulation with neuroinflammatory processes in AUD. EXPERT OPINION: Consistent findings across multiple preclinical studies support continued investigation of mGluR2-targeted therapies as potential interventions for AUD treatment. Restoring glutamatergic homeostasis through mGluR2 modulation may help reduce alcohol seeking behaviors and ultimately improve clinical outcomes in patients with AUD. Future research should also examine the genetic and genomic processes linking neuroinflammation and glutamatergic dysfunction as another avenue for developing novel therapeutic interventions for AUD management.