Glutamatergic targets for new alcohol medications

Abstract

Rationale: An increasingly compelling literature points to a major role for the glutamate system in mediating the effects of alcohol on behavior and the pathophysiology of alcoholism. Preclinical studies indicate that glutamate signaling mediates certain aspects of ethanol's intoxicating and rewarding effects, and undergoes adaptations following chronic alcohol exposure that may contribute to the withdrawal, craving and compulsive drug-seeking that drive alcohol abuse and alcoholism.

Objectives: We discuss the potential for targeting the glutamate system as a novel pharmacotherapeutic approach to treating alcohol use disorders, focusing on five major components of the glutamate system: the N-methyl-D-aspartate (NMDA) receptor and specific NMDA subunits, the glycineB site on the NMDA receptors (NMDAR), L-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid ionotropic (AMPA) and kainate (KAR) receptors, metabotropic receptors (mGluR), and glutamate transporters.

Results: Chronic alcohol abuse produces a hyperglutamatergic state, characterized by elevated extracellular glutamate and altered glutamate receptors and transporters. Pharmacologically manipulating glutamatergic neurotransmission alters alcohol-related behaviors including intoxication, withdrawal, and alcohol-seeking, in rodents and human subjects. Blocking NMDA and AMPA receptors reduces alcohol consumption in rodents, but side-effects may limit this as a therapeutic approach. Selectively targeting NMDA and AMPA receptor subunits (e.g., GluN2B, GluA3), or the NMDAR glycineB site offers an alternative approach. Blocking mGluR5 potently affects various alcohol-related behaviors in rodents, and mGluR2/3 agonism also suppresses alcohol consumption. Finally, glutamate transporter upregulation may mitigate behavioral and neurotoxic sequelae of excess glutamate caused by alcohol.

Conclusions: Despite the many challenges that remain, targeting the glutamate system offers genuine promise for developing new treatments for alcoholism.

Fig. 1

The global burden of alcohol use. Alcohol use ranked third in 2010 risk factors for global disease burden, as measured by disability adjusted life years (DALYs) (left panel), and accounted for 5.5 million deaths worldwide (right panel). Adapted from Lim et al. 2012

Fig. 2

Adaptations of the glutamate system as a result of chronic alcohol abuse. Chronic alcohol abuse produces a “hyperglutamatergic” state during abstinence. This state is characterized by elevated levels of extracellular glutamate and alterations in the expression and localization of various glutamate receptors, including upregulation of NMDARs, and possibly a decrease in calcium-restricting GluA1/2 heteromers in favor of calcium-permeable GluA1 homomers. Key to acronyms/abbreviations: vGLUT vesicular glutamate transporter; mGluR metabotropic glutamate receptor; GluN1, GluN2A, GluN2B NMDAR subunits; GluA1/2, GluA1 AMPAR subunits; VGCC voltage-gated calcium channel; GLAST glutamate transporter subtype (EAAT1); GlyT1 glutamate transporter 1, PSD-95 postsynaptic density 95

Fig. 3

Preclinical examples of glutamate-based approaches to therapeutically targeting various elements of alcoholism. Potentiating alcohol intoxication: mice administered the NMDAR antagonist, MK-801, show markedly prolonged sedative/hypnotic responses to ethanol (Palachick et al. 2008). Alleviating alcohol withdrawal: rats infused with the AMPAR antagonist DNQX directly into amygdala exhibited less ethanol-induced withdrawal anxiety (Lack et al. 2007). Blunting alcohol craving: mice with deletion of the NMDAR anchoring protein PSD-95 consumed less ethanol at baseline and after deprivation (Camp et al. 2011). Reducing alcohol-seeking and consumption: mice with deletion of the NMDAR anchoring protein PSD-95 consumed less ethanol at baseline and after deprivation (Camp et al. 2011). Blunting alcohol craving: rats administered the mGluR5 antagonist, MPEP, reduced ethanol-seeking (black bars active lever presses) during cue-induced reinstatement (Cowen et al. 2003). Preventing habitual and compulsive alcohol consumption: rats administered the GlyT1 transporter blocker, Org25935, decreased “compulsive-like” alcohol consumption after a history of chronic ethanol treatment/deprivation (Vengeliene et al. 2010). Arresting alcohol-induced neurodegeneration: rats treated with the mGluR2/3 agonist, LY379268, were protected against binge ethanol-induced increased in TGF-β2-immunoreactivity, a measure of neurodegeneration. Adapted from Cippitelli et al. 2010