Glutamatergic medications for the treatment of drug and behavioral addictions

Abstract

Historically, most pharmacological approaches to the treatment of addictive disorders have utilized either substitution-based methods (i.e., nicotine replacement or opioid maintenance) or have targeted monoaminergic or endogenous opioidergic neurotransmitter systems. However, substantial evidence has accumulated indicating that ligands acting on glutamatergic transmission are also of potential utility in the treatment of drug addiction, as well as various behavioral addictions such as pathological gambling. The purpose of this review is to summarize the pharmacological mechanisms of action and general clinical efficacy of glutamatergic medications that are currently approved or are being investigated for approval for the treatment of addictive disorders. Medications with effects on glutamatergic transmission that will be discussed include acamprosate, N-acetylcysteine, d-cycloserine, gabapentin, lamotrigine, memantine, modafinil, and topiramate. We conclude that manipulation of glutamatergic neurotransmission is a relatively young but promising avenue for the development of improved therapeutic agents for the treatment of drug and behavioral addictions.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1

Putative glutamatergic mechanisms of action of 8 anti-addiction medications. Acamprosate - The molecular target(s) of acamprosate is still uncertain, but several studies have indicated it modulates the activity of NMDA receptors and restores balance between excitatory and inhibitory neurotransmission that is altered by chronic alcohol consumption. N-acetylcysteine (NAC) is a cystine prodrug that stimulants the cystine-glutamate exchanger (xc-) on glia to normalize extracellular levels of glutamate, which are reduced in the nucleus accumbens during cocaine withdrawal. This normalization of extracellular glutamate levels restores glutamatergic tone on release-inhibiting presynaptic mGluR2/3 receptors, which in turn inhibits the ability of exposure to cocaine (and perhaps cocaine-associated cues) to elevate extracellular glutamate and evoke cocaine craving or relapse. D-cycloserine (DCS) is a partial agonist at the glyine co-agonist binding site on NR1 subunits that are intrinsic to all NMDA receptors, and thus DCS potentiates cation influx through the NMDA receptor complex. Modafinil has numerous actions on neurons and its precise molecular targets have yet to be identified. However, several microdialysis studies have shown that modafinil increases extracellular levels of glutamate in various brain regions. Gabapentin, lamotrigine, topiramate are anticonvulsants that have numerous mechanisms of action, one of which is the reduction of the release of glutamate by blocking cation influx through presynaptic Na+ and Ca2+ channels. Topiramate has the unique ability to also antagonize GluR5-containing AMPA receptors. Memantine is a non-competitive NMDA receptor antagonist.