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 relatively young but promising avenue for the development of improved therapeutic agents for the treatment of drug and behavioral addictions.

Relapse is one of the most problematic aspects in the treatment of alcoholism and is often triggered by alcohol-associated environmental cues. Evidence indicates that glutamate neurotransmission plays a critical role in cue-induced relapse-like behavior, as inhibition of glutamate neurotransmission can prevent reinstatement of alcohol-seeking behavior. However, few studies have examined specific changes in extracellular glutamate levels in discrete brain regions produced by exposure to alcohol-associated cues. The purpose of this study was to use glutamate oxidase (GluOx)-coated biosensors to monitor changes in extracellular glutamate in specific brain regions during cue-induced reinstatement of alcohol-seeking behavior. Male Wistar rats were implanted with indwelling jugular vein catheters and intracerebral guide cannula aimed at the basolateral amygdala (BLA) or nucleus accumbens (NAc) core, and then trained to selfadminister alcohol intravenously. A separate group of animals was trained to self-administer food pellets. Each reinforcer was accompanied by the presentation of a light/tone stimulus. Following stabilization of responding for alcohol or food reinforcement and subsequent extinction training, animals were implanted with precalibrated biosensors and then underwent a 1 hr cue-induced reinstatement testing period. As determined by GluOx-coated biosensors, extracellular levels of glutamate were increased in the BLA and NAc core during cue-induced reinstatement of alcoholseeking behavior. The cumulative change in extracellular glutamate in both regions was significantly greater for cue-induced reinstatement of alcohol-seeking behavior versus that of food-seeking behavior. These results indicate that increases in glutamate transmission in the BLA and NAc core may be a neurochemical substrate of cue-evoked alcohol-seeking behavior.

Pharmacological blockade of the type 5 metabotropic glutamate receptor (mGluR5) attenuates cue-induced reinstatement of ethanol-seeking behavior, yet the brain regions involved in these effects are not yet known. The purpose of the present study was to determine if local blockade of mGluR5 receptors in the basolateral amygdala (BLA) and/or the nucleus accumbens (NAc), two brain regions known to be involved in stimulus-reward associations, attenuates the reinstatement of ethanol-seeking behavior induced by ethanol-paired cues. As a control for possible non-specific effects, the effects of mGluR5 blockade in these regions on cue-induced reinstatement of sucrose-seeking were also assessed. Male Wistar rats were implanted with bilateral microinjection cannulae aimed at the BLA or NAc. Following recovery, animals were trained to self-administer ethanol (10% w/v) or 45 mg sucrose pellets on an FR1 schedule of reinforcement in 30 min daily sessions using a sucrose fading procedure. Following stabilization of responding, animals underwent extinction training. Next, animals received infusions of vehicle or the selective mGluR5 antagonist MTEP (3 μg/μl) into the BLA or NAc prior to cue-induced reinstatement testing sessions. mGluR5 blockade eliminated cue-induced reinstatement of alcohol-but not sucrose-seeking behavior. Results from this study indicate that mGluR5 receptors in the BLA and NAc mediate cue-induced reinstatement of ethanol-seeking behavior, and provide two potential neuroanatomical sites of action where systemically administered mGluR5 antagonists attenuate cue-induced reinstatement. These data are consistent with previous findings that cue-induced reinstatement of ethanol-seeking increases neuronal activity and glutamatergic transmission in these two regions.

Extinction of classically and instrumentally conditioned behaviors, such as conditioned fear and drug-seeking behavior, is a process of active learning, and recent studies indicate that potentiation of glutamatergic transmission facilitates extinction learning. In this study we investigated the effects of the type 5 metabotropic glutamate receptors (mGluR5) positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the extinction of cocaine-seeking behavior in rats with a history of intravenous cocaine self-administration. To assess its effects on acquisition and consolidation of extinction learning, CDPPB (60 mg/kg) or vehicle was administered either 20 min prior to, or immediately following, each of 10 extinction sessions, respectively. When administered prior to each extinction session, CDPPB produced a significant reduction in the number of active lever presses on all 10 days of extinction training as compared to vehicle-treated animals. When administered following each extinction session, a significant reduction in the number of active lever presses was observed on the 2nd through 10th day of extinction. Both treatment regimens also reduced the number of extinction training sessions required to meet extinction criteria. Pre- or post-extinction training administration of CDPPB did not alter responding on the inactive lever and had no effects on open field locomotor activity. These data indicate that positive allosteric modulation of mGluR5 receptors facilitates the acquisition and consolidation of extinction learning following cocaine self-administration, and may provide a novel pharmacological approach to enhancing extinction learning when combined with cue exposure therapy for the treatment of cocaine addiction.

Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated that type 5 metabotropic glutamate receptors (mGluR5) are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson’s disease, and gastroesophageal reflux disease. However, in recent years, the development of positive allosteric modulators (PAMs) of the mGluR5 receptor have revealed that allosteric activation of this receptor may also be of potential therapeutic benefit for the treatment of other CNS disorders, including schizophrenia, cognitive deficits associated with chronic drug use, and deficits in extinction learning. Here we summarize the discovery and characterization of various mGluR5 PAMs, with an emphasis on those that are systemically active. We will also review animal studies showing that these molecules have potential efficacy as novel antipsychotic agents. Finally, we will summarize findings that suggest that mGluR5 PAMs have pro-cognitive effects such as the ability to enhance synaptic plasticity, improve performance in various learning and memory tasks, including extinction of drug-seeking behavior, and reverse cognitive deficits produced by chronic drug use.

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.

Historically, brain catecholamine systems have been the primary focus of studies examining the neural substrates of drug addiction. In the past two decades, however, a wealth of evidence has accumulated indicating a pivotal role for glutamatergic neurotransmission in mediating addictive behaviors as well as long-term neuroplasticity associated with chronic drug use. As a result, there has been increased interest in developing glutamate-based therapies for the treatment of addictive disorders. Metabotropic glutamate (mGlu) receptors are classified into subcategories designated as Group I (mGlu1 and mGlu5), Group II (mGlu2 and mGlu3), and Group III (mGlu4, mGlu6, mGlu7, and mGlu8), and have received a great deal of attention due to their mediation of slower modulatory excitatory neurotransmission. Pharmacological ligands targeting these receptors have demonstrated reduced incidences of excitotoxicity or severe adverse side effects as compared to those targeting ionotropic glutamate (iGlu) receptors. Behavioral genetic and pharmacological studies have explored the role of individual mGlu receptor subtypes in regulating various addiction-related behaviours and several mGlu receptor ligands have been the subject of clinical testing for other medical conditions.

Extinction of drug-seeking behavior is a form of new and active learning. Facilitation of extinction learning is of clinical interest since cue exposure therapies for the treatment of addiction have largely been unsuccessful in preventing relapse, primarily due to the context specificity of extinction learning. Recently, several studies have shown that potentiation of glutamatergic transmission can facilitate extinction learning in rodent models of cocaine addiction. In this study we investigated the effects of the type 5 metabotropic glutamate receptor (mGluR5) positive allosteric modulator (PAM) 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the extinction and contextual reinstatement of methamphetamine-seeking behavior. Rats were trained and allowed to self-administer methamphetamine (0.1 mg/kg/infusion) in 2 hr daily sessions in Context A where self-administration chambers had distinct tactile, visual, auditory, and olfactory cues. Next, CDPPB (60 mg/kg) or vehicle was administered prior to subsequent extinction training sessions that were conducted in modified self-administration chambers (Context B) that were Context A. Following 16 days of extinction training in Context B, animals were placed back in Context A for assessment of contextual reinstatement of methamphetamine-seeking behavior. CDPPB failed to produce significant reductions in extinction responding or in the magnitude of contextual reinstatement of methamphetamine-seeking compared to vehicle treated controls. We postulate that numerous factors, including methamphetamine-induced changes in mGluR5 receptor expression or function, may have contributed to the observed lack of effects. Although these findings initially suggest that mGluR5 PAMs may be ineffective in facilitating extinction learning or preventing context-induced relapse in methamphetamine addiction, additional studies are warranted examining effects of other mGluR5 PAMs, particularly those with improved pharmacological properties and devoid of potential side effects at higher doses.