Glutamatergic Targets for Enhancing Extinction Learning in Drug Addiction

R.      M. Cleva; J.      T. Gass; J.      J. Widholm; M.      F. Olive

doi:10.2174/157015910793358169

Abstract

The persistence of the motivational salience of drug-related environmental cues and contexts is one of the most problematic obstacles to successful treatment of drug addiction. Behavioral approaches to extinguishing the salience of drug-associated cues, such as cue exposure therapy, have generally produced disappointing results which have been attributed to, among other things, the context specificity of extinction and inadequate consolidation of extinction learning. Extinction of any behavior or conditioned response is a process of new and active learning, and increasing evidence suggests that glutamatergic neurotransmission, a key component of the neural plasticity that underlies normal learning and memory, is also involved in extinction learning. This review will summarize findings from both animal and human studies that suggest that pharmacological enhancement of glutamatergic neurotransmission facilitates extinction learning in the context of drug addiction. Pharmacological agents that have shown potential efficacy include NMDA partial agonists, mGluR5 receptor positive allosteric modulators, inhibitors of the GlyT1 glycine transporter, AMPA receptor potentiators, and activators of the cystine-glutamate exchanger. These classes of cognition-enhancing compounds could potentially serve as novel pharmacological adjuncts to cue exposure therapy to increase success rates in attenuating cue-induced drug craving and relapse.

Keywords: Extinction, learning, glutamate, NMDA, AMPA, mGluR5, GlyT1 glycine transporter, receptor potentiator, allosteric modulator, cystine-glutamate exchanger, Drug addiction, compulsive drug intake, drug-seeking, intake. Chronic, drug's effects, drug craving, hyper-salient, drug-related stimuli, neural circuits, long-term potentiation, long-term depression, neurotransmission, hyperexcitability, excito-toxicity, neuroanatomical substrates, synaptic plasticity, D-cycloserine, anxiety disorders, de novo protein synthesis, intracellular signaling, pro-mnemonic, N-methyl-D-asparate, baso-lateral amygdala, drug-associated, animal models, conditioned place preference, intra-venous drug self-administration, indwelling intravenous catheter, reinstatement, prefrontal cortex, campus, amygdala, amphetamine, cocaine-induced reinstatement, glutamatergic synapse, ionotropic gluta-mate receptors, methylisoxazole-4-propionic acid, kainic acid, D-serine, glycine, GlyT1, GlyT2, GluRA-D, GluR1, mGluRs, GPCRs, excitatory amino acid transport-ers (EAATs), excitotoxicity, fluorobenzylidene, dioxoisoindolin-2