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.

Keywords: Alcohol use disorder; bed nucleus of the stria terminalis; metabotropic glutamate receptor; nucleus accumbens; prefrontal cortex; synaptic plasticity.

Figure 1.

Simplified neurocircuitry underlying normal and pathophysiological ethanol seeking. (A) Basic motor circuit supporting initiation of ethanol seeking. Dopaminergic midbrain areas project to the dorsal and ventral striatum to promote motivated behaviors. Dopamine promotes the activation of dopamine receptor subtype 1 (D1)-expressing “direct pathway” medium spiny neurons (MSNs). D1 MSNs send inhibitory afferents back to the VTA and SNC, where they inhibit local GABAergic neurons and disinhibit dopamine neurons. In contrast, striatal dopamine release inhibits D2-MSNs, thereby relieving inhibition on the pallidum. Decreased output from the pallidum disinhibits the thalamus, the striatum, and the MC. The MC and pallidum provide the major outputs of this circuit to the brainstem to promote the initiation of ethanol seeking. (B) Impaired top-down control and excessive compulsive ethanol seeking. Dysregulation of the cortical inputs onto the striatum is believed to underlie the loss of control observed in AUD. Decreased function of the IL PFC inputs to the NAC shell and enhanced activity of the VH and PL PFC inputs are thought to mediate excessive motivation to seek ethanol as well as reinstatement. Alterations in the OFC projections to the dorsal striatum are also believed to play a part in habitual, compulsive-like ethanol seeking. (C) Enhanced bottom-up stress reactivity in AUD. The extended amygdala plays a key role in the regulation of emotions and stress response, particularly in the context of ethanol seeking. Excitatory projections from the BLA to the PFC, NAC, and BNST may each be important in promoting stress-induced reinstatement. The BNST is composed of both excitatory and inhibitory projection neurons that modulate the function of the NAC and also the dopaminergic midbrain areas. Finally, the enhanced activity of the IC is thought to be involved in stress-related ethanol seeking, and its projections to the NAC and BNST may be particularly important for these effects.

Figure 2.

Contrasting mechanisms of mGlu receptor plasticity across excitatory synapses in the limbic system. (A) Plasticity mechanisms in the PFC. mGlu₂ and mGlu₄ each inhibit glutamate release in the PFC. Whether mGlu₇ and mGlu₈ function similarly at these synapses has not been determined. On the postsynaptic side, activation of mGlu₃ initiates a cascade of signaling events that culminates with AMPA receptor internalization. This process depends on the activation of mGlu₅ and PI3K. mGlu₅ activation here has also been shown to promote the production of 2-AG, retrograde activation of CB1, and inhibition of glutamate release probability. Furthermore, mGlu₅ inhibits SK channels, relieving an inhibitory constraint on NMDA receptors and promoting additional mechanisms of plasticity not depicted here. (B) Plasticity mechanisms in the NAC. Activation of mGlu_2/3 decreases glutamate release probability, but the subtype(s) involved has not been determined conclusively. In normal animals, activation of mGlu leads to a presynaptic LTD through the activation of CB1. In the core subregion, this phenomenon is specific to D2 MSNs and coincides with an AEA- and TRPV1-dependent internalization of AMPA receptors. However, in animals conditioned with chronic cocaine self-administration, postsynaptic LTD mediated by mGlu₁ can emerge. This depotentiation requires the activation of PKC and internalization of GluA2-lacking AMPA receptors, and it is unknown whether similar alterations to plasticity may emerge following ethanol exposure. (C) Plasticity mechanisms in the BNST. Activation of presynaptic group II or group III mGlu receptors transiently inhibits glutamate release probability. mGlu₈ activation is sufficient for this effect, but the contribution of the other subtypes is not well understood. Postsynaptic mGlus induces ERK1-dependent AMPA receptor internalization. Activation of group I mGlu receptors also induces CB1-dependent LTD; however, the subtype and specific endocannabinoid species involved have not been determined.