Glutamate Transporter GLT-1 as a Therapeutic Target for Substance Use Disorders

Abstract

The development of new treatments for substance use disorders requires identification of targetable molecular mechanisms. Pathology in glutamatergic neurotransmission system in brain reward circuitry has been implicated in relapse to multiple classes of drugs. Glutamate transporter 1 (GLT-1) crucially regulates glutamatergic signaling by removing excess glutamate from the extrasynaptic space. The purpose of this review is to highlight the effects of addictive drug use on GLT-1 and glutamate uptake, and using GLT-1 as a target in addiction pharmacotherapy. Cocaine, opioids, ethanol, nicotine, amphetamines, and cannabinoids each affect GLT-1 expression and glutamate uptake, and restoring GLT-1 expression with N-acetylcysteine or ceftriaxone shows promise in correcting pre-clinical and clinical manifestations of drug addiction.

Reversal of morphine-induced cell-type–specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement

“…Here we show that prior optogenetic stimulation of ILC-NAc shell terminals using a protocol known to produce LTD in NAc MSNs produces a depotentiation of morphine synaptic strength in D1R-MSNs and prevents morphine-induced reinstatement of place preference. Previous work has shown that reversible inactivation of the NAc shell during testing can block heroinprimed reinstatement (18). Furthermore, inactivation of the ILC in conjunction with D1R antagonism in the NAc shell during testing attenuates context-induced reinstatement of heroin seeking (19).…”

“…Conversely, compounds that increase GLT-1 expression, such as the antibiotic ceftriaxone, reduce cocaine and heroin seeking (17,18). Although these latter effects have been attributed to normalization of extracellular glutamate levels following cocaine seeking, the effect of ceftriaxone on opioid-induced changes in NAc MSN synaptic strength and function remains unclear.…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…We recently reviewed the existing clinical trials of GLT-1-modulating agents in the treatment of drug addiction (Roberts-Wolfe and Kalivas, 2015) and summarize key points from that review here. GLT-1 is the primary regulator of extrasynaptic glutamate concentrations in the forebrain.…”

“…NAC is well tolerated, does not have abuse potential, and does not appear to have toxic interaction effects with drugs of abuse. Several clinical trials have investigated NAC as a therapy for drug addiction (Roberts-Wolfe and Kalivas, 2015).…”

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“…These include not only the Group II and Group III glutamate metabotropic receptors but also cholinergic (nicotinic and muscarinic) receptors, adenosine (A1), kappa opioid, γ-amino butyric acid (GABA B), cholecystokinin and neuropeptide Y (Y2) receptors. 54,55 Glutamate mainly show its actions through ligandgated ion channel (ionotropic) receptors, including the N-methyl-d-aspartate (NMDA), kainate, andamino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtypes, and G protein-coupled metabo-tropic receptors (mGluR1-8). 56 Each NMDAR complex consists of four (occasionally five) subunits: two NR1 subunits (generated by alternative splicing of a single gene, NR1), and two or three NR2 subunits (coded by four related genes, NR2 A-D).…”