Advances in translating mGlu2 and mGlu3 receptor selective allosteric modulators as breakthrough treatments for affective disorders and alcohol use disorder

Abstract

Metabotropic glutamate (mGlu) receptors are promising targets for the treatment of affective disorders and alcohol use disorder (AUD). Nonspecific ligands for Group II (mGlu₂ and mGlu₃) mGlu receptors have demonstrated consistent therapeutic potential for affective disorders in preclinical models. Disentangling the specific roles of mGlu₂ versus mGlu₃ receptors in these effects has persisted as a major challenge, in part due to pharmacological limitations. However, the recent development of highly specific allosteric modulators for both mGlu₂ and mGlu₃ receptors have enabled straightforward and rigorous investigations into the specific function of each receptor. Here, we review recent experiments using these compounds that have demonstrated both similar and distinct receptor functions in behavioral, molecular, and electrophysiological measures associated with basal function and preclinical models of affective disorders. Studies using these selective drugs have demonstrated that mGlu₂ is the predominant receptor subclass involved in presynaptic neurotransmitter release in prefrontal cortex. By contrast, the activation of postsynaptic mGlu₃ receptors induces a cascade of cellular changes that results in AMPA receptor internalization, producing long-term depression and diminishing excitatory drive. Acute stress decreases the mGlu₃ receptor function and dynamically alters transcript expression for both mGlu₂ (Grm2) and mGlu₃ (Grm3) receptors in brain areas involved in reward and stress. Accordingly, both mGlu₂ and mGlu₃ negative allosteric modulators show acute antidepressant-like effects and potential prophylactic effects against acute and traumatic stressors. The wide array of effects displayed by these new allosteric modulators of mGlu₂ and mGlu₃ receptors suggest that these drugs may act through improving endophenotypes of symptoms observed across several neuropsychiatric disorders. Therefore, recently developed allosteric modulators selective for mGlu₂ or mGlu₃ receptors show promise as potential therapeutics for affective disorders and AUD.

Keywords: Drug discovery; Electrophysiology; G protein-coupled receptor; Gene expression; Prelimbic cortex; Synaptic plasticity.