Metabotropic Glutamate Receptors in Alcohol Use Disorder: Physiology, Plasticity, and Promising Pharmacotherapies

Abstract

Developing efficacious treatments for alcohol use disorder (AUD) has proven difficult. The insidious nature of the disease necessitates a deep understanding of its underlying biology as well as innovative approaches to ameliorate ethanol-related pathophysiology. Excessive ethanol seeking and relapse are generated by long-term changes to membrane properties, synaptic physiology, and plasticity throughout the limbic system and associated brain structures. Each of these factors can be modulated by metabotropic glutamate (mGlu) receptors, a diverse set of G protein-coupled receptors highly expressed throughout the central nervous system. Here, we discuss how different components of the mGlu receptor family modulate neurotransmission in the limbic system and other brain regions involved in AUD etiology. We then describe how these processes are dysregulated following ethanol exposure and speculate about how mGlu receptor modulation might restore such pathophysiological changes. To that end, we detail the current understanding of the behavioral pharmacology of mGlu receptor-directed drug-like molecules in animal models of AUD. Together, this review highlights the prominent position of the mGlu receptor system in the pathophysiology of AUD and provides encouragement that several classes of mGlu receptor modulators may be translated as viable treatment options.

Mechanisms underlying prelimbic prefrontal cortex mGlu3/mGlu5-dependent plasticity and reversal learning deficits following acute stress

“…Specifically, the PAM potentiates Ca 2+ mobilization and hippocampal LTD without directly enhancing N-methyl-D-aspartate (NMDA) receptor function. Therefore, although mGlu 5 has been intimately linked with NMDA receptor-dependent plasticity (Joffe et al, 2018), the molecular pharmacology suggests those signaling pathways are likely not involved in the effects observed here. In addition, Balu et al (Balu et al, 2016) reported that VU0409551 treatment enhances PL-PFC Akt phosphorylation in a genetic model of schizophrenia-like deficits as well as in control mice.…”

The Toll‐Like Receptor 3 Agonist Poly(I:C) Induces Rapid and Lasting Changes in Gene Expression Related to Glutamatergic Function and Increases Ethanol Self‐Administration in Rats

“…Numerous studies have suggested that neuroimmune activation may play an important role in the development of addiction (for review, see (Coleman and Crews 2018)). Further, the identified interaction with mGlu2/3 is significant given the growing interest in mGluR2/3 as a therapeutic target of AUDs (Joffe et al 2018). Furthermore, ethanol induces many of the same effects in the brain that a viral pathogen would (i.e., increases in TLRs and other markers of inflammation; (Crews et al 2013; Crews and Vetreno 2014; 2016; Frank et al 2015; Hutchinson et al 2010; Knapp and Crews 1999; McCarthy et al 2017; Northcutt et al 2015)).…”

“…To this end, there is interest in understanding the potential contribution of Group II metabotropic glutamate receptors (mGluRs), along with excitatory amino acid transporter 2 (EAAT2) also known as solute carrier family 1 member 2(SLC1A2) and glutamate transporter 1 (GLT1), for their role in AUDs (Joffe et al 2018). These Gi-coupled receptors are located both pre- (mGluR2 and mGluR3) and post- (mGluR3) synaptically and modulate glutamate release, in part by preventing excitotoxicity (Cartmell and Schoepp 2000; Conn and Pin 1997; Forsythe and Barnes-Davies 1997; Scanziani et al 1997; Schoepp 2001).…”

Neuropharmacological Insight from Allosteric Modulation of mGlu Receptors

“…For example, a recent study has provided evidence for mGlu 5 in sleep/wake architecture, suggesting that mGlu 5 allosteric modulators may have potential to remedy certain sleep disorders [66]. Certainly, investigation of mGlu allosteric modulators for substance use disorders [67], epilepsy [68], major depressive disorder [69], and Alzheimer's disease [70] are contexts in which there is exciting work being accomplished within the field of allosteric modulators and mGlu receptors. As the drug discovery process is a circular method, continued research efforts will likely lead to even more insights into the neuropharmacology surrounding mGlu allosteric modulators and their usefulness as therapeutics in CNS disorders.…”