Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration (original) (raw)

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

The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goaldirected behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking.Anumber of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These druginduced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.

Role of nucleus accumbens glutamatergic plasticity in drug addiction

Neuropsychiatric Disease and Treatment, 2013

Substance dependence is characterized by a group of symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). These symptoms include tolerance, withdrawal, drug consumption for alleviating withdrawal, exaggerated consumption beyond original intention, failure to reduce drug consumption, expending a considerable amount of time obtaining or recovering from the substance's effects, disregard of basic aspects of life (for example, family), and maintenance of drug consumption, despite facing adverse consequences. The nucleus accumbens (NAc) is a brain structure located in the basal forebrain of vertebrates, and it has been the target of addictive drugs. Different neurotransmitter systems at the level of the NAc circuitry have been linked to the different problems of drug addiction, like compulsive use and relapse. The glutamate system has been linked mainly to relapse after drug-seeking extinction. The dopamine system has been linked mainly to compulsive drug use. The glutamate homeostasis hypothesis centers around the dynamics of synaptic and extrasynaptic levels of glutamate, and their impact on circuitry from the prefrontal cortex (PFC) to the NAc. After repetitive drug use, deregulation of this homeostasis increases the release of glutamate from the PFC to the NAc during drug relapse. Glial cells also play a fundamental role in this hypothesis; glial cells shape the interactions between the PFC and the NAc by means of altering glutamate levels in synaptic and extrasynaptic spaces. On the other hand, cocaine self-administration and withdrawal increases the surface expression of subunit glutamate receptor 1 (GluA1) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at the level of the NAc. Also, cocaine self-administration and withdrawal induce the formation of subunit glutamate receptor 2 (GluA2), lacking the Ca 2+-permeable AMPA receptors (CP-AMPARs) at the level of the NAc. Antagonism of the CP-AMPARs reduces cravings. It is necessary to pursue further exploration of the AMPA receptor subunit composition and variations at the level of the NAc for a better understanding of glutamatergic plastic changes. It is known that cocaine and morphine are able to induce changes in dendritic spine morphology by modifying actin cycling. These changes include an initial increase in spine head diameter and increases in AMPA receptor expression, followed by a second stage of spine head diameter retraction and reduction of the AMPA receptors' expression in spines. Besides glutamate and dopamine, other factors, like brain-derived neurotrophic factor (BDNF), can influence NAc activity and induce changes in dendritic spine density. BDNF also induces drug-related behaviors like self-administration and relapse. Neither apoptosis nor neurogenesis plays a relevant role in the neurobiological processes subjacent to cocaine addiction in adults (rodent or human). Different therapeutic drugs like N-acetylcysteine (NAC), modafinil, acamprosate, and topiramate have been tested in preclinical and/or clinical models for alleviating drug relapse. Moreover, these therapeutic drugs target the glutamatergic circuitry between the PFC and the NAc. NAC and acamprosate have shown inconsistent results in clinical trials. Modafinil and topiramate have shown some success, but more clinical trials are necessary. Based on the current review

A Shift in the Role of Glutamatergic Signaling in the Nucleus Accumbens Core with the Development of an Addicted Phenotype

Biological Psychiatry, 2014

Background-While dopamine signaling in the nucleus accumbens (NAc) plays a wellestablished role in motivating cocaine use in early "non-addicted" stages, recent evidence suggests that other signaling pathways may be critical once addiction has developed. Given the importance of glutamatergic signaling in the NAc for drug-seeking and relapse, here we examined its role in motivating cocaine self-administration under conditions known to produce either a "non-addicted" or an "addicted" phenotype. Methods-Following acquisition, male and female Sprague Dawley rats were given either short access (3 fixed-ratio 1 sessions, 20 infusions/day) or extended 24-hr access (10 days; 4 trials/hr; up to 96 infusions/day) to cocaine. Following a 14-day abstinence period, motivation for cocaine was assessed under a progressive-ratio schedule, and once stable, the effects of intra-NAc infusions of the glutamate AMPA/KA receptor antagonist CNQX (0.0, 0.01, 0.03, 0.1 μg/side) were determined. As an additional measure for the development of an addicted phenotype, separate groups of rats were screened under an extinction/cue-induced reinstatement procedure following abstinence from short versus extended access self-administration. Results-Motivation for cocaine and levels of extinction and reinstatement responding were markedly higher following extended versus short access self-administration confirming the development of an addicted phenotype in the extended access group. CNQX dose-dependently reduced motivation for cocaine in the extended access group, but was without effect in the short access group. Conclusions-These results suggest that the role of glutamatergic signaling in the NAc, though not essential for motivating cocaine use in "non-addicted" stages, becomes critical once addiction has developed.

Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats

Addiction Biology, 2011

The functional integrity of the nucleus accumbens (NAC) core and shell is necessary for contextual cocaine-seeking behavior in the reinstatement animal model of drug relapse; however, the neuropharmacological mechanisms underlying this phenomenon are poorly understood. The present study evaluated the contribution of metabotropic glutamate receptor subtype 1 (mGluR1) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor populations to drug context-induced reinstatement of cocaine-seeking behavior. Rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after JNJ16259685 (mGluR1 antagonist: 0.0, 0.6, or 30 pg/0.3 μl/hemisphere) or CNQX (AMPA/kainate receptor antagonist: 0.0, 0.03, or 0.3 μg/0.3 μl/hemisphere) administration into the NAC core, medial or lateral NAC shell, or the ventral caudate-putamen (vCPu, anatomical control). JNJ16259685 or CNQX in the NAC core dose-dependently impaired contextual cocaine-seeking behavior relative to vehicle. Conversely, CNQX, but not JNJ16259685, in the lateral or medial NAC shell attenuated, whereas CNQX or JNJ16259685 in vCPu failed to inhibit, this behavior. The manipulations failed to alter instrumental behavior in the extinction context, general motor activity, or food-reinforced instrumental behavior in control experiments. Thus, glutamatemediated changes in drug context-induced motivation for cocaine involve distinct neuropharmacological mechanisms within the core and shell subregions of the NAC, with the stimulation of mGlu1 and AMPA/kainate receptors in the NAC core and the stimulation of AMPA/kainate, but not mGlu1, receptors in the NAC shell being necessary for this phenomenon.

Subregion-specific role of glutamate receptors in the nucleus accumbens on drug context-induced reinstatement of cocaine-seeking behavior in rats: Glutamate and cocaine seeking

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2012

The functional integrity of the nucleus accumbens (NAC) core and shell is necessary for contextual cocaine-seeking behavior in the reinstatement animal model of drug relapse; however, the neuropharmacological mechanisms underlying this phenomenon are poorly understood. The present study evaluated the contribution of metabotropic glutamate receptor subtype 1 (mGluR1) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor populations to drug context-induced reinstatement of cocaine-seeking behavior. Rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after JNJ16259685 (mGluR1 antagonist: 0.0, 0.6, or 30 pg/0.3 μl/hemisphere) or CNQX (AMPA/kainate receptor antagonist: 0.0, 0.03, or 0.3 μg/0.3 μl/hemisphere) administration into the NAC core, medial or lateral NAC shell, or the ventral caudate-putamen (vCPu, anatomical control). JNJ16259685 or CNQX in the NAC core dose-dependently impaired contextual cocaine-seeking behavior relative to vehicle. Conversely, CNQX, but not JNJ16259685, in the lateral or medial NAC shell attenuated, whereas CNQX or JNJ16259685 in vCPu failed to inhibit, this behavior. The manipulations failed to alter instrumental behavior in the extinction context, general motor activity, or food-reinforced instrumental behavior in control experiments. Thus, glutamatemediated changes in drug context-induced motivation for cocaine involve distinct neuropharmacological mechanisms within the core and shell subregions of the NAC, with the stimulation of mGlu1 and AMPA/kainate receptors in the NAC core and the stimulation of AMPA/kainate, but not mGlu1, receptors in the NAC shell being necessary for this phenomenon.

The good and bad news about glutamate in drug addiction

Journal of psychopharmacology (Oxford, England), 2016

In 1998 we published a perspective review describing how drug-induced neuroadaptations might serve towards understanding drug craving. We proposed experimental perspectives to help discern data relevant to long-lasting brain changes, and to distinguish dopamine-related changes that were largely pharmacological from glutamatergic changes that were based on drug-environment associations. These perspectives are embedded in drug abuse research, and the last 18 years has witnessed marked development in understanding addiction-associated corticostriatal glutamate plasticity. Here we propose three new perspectives on how the field might approach integrating and using the emerging data on glutamatergic adaptations. (1) Consider adaptations produced in kind across drug classes as most useful towards understanding shared characteristics of addiction, such as relapse. (2) Consider how drug-induced changes in glia and the extracellular matrix may contribute to synaptic alterations. (3) Make mea...

Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction

Frontiers in Cellular Neuroscience, 2015

Addictive drugs remodel the brain's reward circuitry, the mesocorticolimbic dopamine (DA) system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review highlights the synaptic modifications that are induced by in vivo exposure to addictive drugs and describes how these drug-induced synaptic changes may contribute to the different components of addictive behavior, such as compulsive drug use despite negative consequences and relapse. Initially, exposure to an addictive drug induces synaptic changes in the ventral tegmental area (VTA). This drug-induced synaptic potentiation in the VTA subsequently triggers synaptic changes in downstream areas of the mesocorticolimbic system, such as the nucleus accumbens (NAc) and the prefrontal cortex (PFC), with further drug exposure. These glutamatergic synaptic alterations are then thought to mediate many of the behavioral symptoms that characterize addiction. The later stages of glutamatergic synaptic plasticity in the NAc and in particular in the PFC play a role in maintaining addiction and drive relapse to drug-taking induced by drugassociated cues. Remodeling of PFC glutamatergic circuits can persist into adulthood, causing a lasting vulnerability to relapse. We will discuss how these neurobiological changes produced by drugs of abuse may provide novel targets for potential treatment strategies for addiction.

The Story of Glutamate in Drug Addiction and of N-Acetylcysteine as a Potential PharmacotherapyGlutamate and N-Acetylcysteine in Drug AddictionViewpoint

The prevalence and impact of drug addiction on society are staggering. The abuse of alcohol, tobacco, and illicit drugs accounts for approximately 10% of the global burden of disease, and for the United States, it is estimated that substance use disorders affect 20.4 million individuals. 1 Despite the deleterious economic and social consequences of drug use, approved medications to treat substance use disorders are few or absent depending on the drug. We and others have explored the possibility that dysregulation in prefrontal and allocortical (amygdala and hippocampus) glutamatergic inputs to the basal ganglia may be a mechanism responsible for relapse that is shared between classes of addictive drugs, as well as other disorders characterized by maladaptive compulsive behavior. Herein, we describe the benchto-bedside chronology of preclinical discovery and clinical trials that led to the cysteine prodrug N-acetylcysteine being evaluated for the treatment of substance abuse and compulsive disorders. Drug addiction is a chronic brain disorder characterized by compulsive drug use that occurs at the expense of other biologically adaptive activities. The transition from casual to compulsive drug use and the enduring propensity to relapse is maintained by longlasting neuroadaptations in specific brain circuits. For example, it is well established that all drugs of abuse enhance dopamine neurotransmission to reinforce and establish drug-seeking behavior. Although less thoroughly studied, we and others have shown that the enduring vulnerability to relapse to drug use involves the recruitment of glutamatergic projections to the ventral striatum, in particular the nucleus accumbens, and is associated with enduring changes in glutamatergic synaptic transmission. Glutamatergic inputs from the amygdala, hippocampus, and prefrontal cortex to the accumbens regulate adaptive behavioral responses by integrating environmental stimuli with memories of related experiences. 2 Thus, by producing enduring changes in glutamatergic synapses in the accumbens, longterm use of addictive drugs impairs the ability of an individual to inhibit drug seeking and use, ultimately producing the persistent relapsing disorder that characterizes drug addiction. Animal models of drug addiction have shown that drug seeking is associated with increased glutamate release from prefrontal projections into the nucleus accumbens. When large amounts of glutamate are released, the excess spills out of the synaptic cleft and activates extrasynaptic glutamate receptors (Figure). Demonstrating spillover of synaptically released glutamate in animals trained to self-administer cocaine, heroin, nicotine, or alcohol was an important indication that alterations in glutamatergic synapses might be re

The Story of Glutamate in Drug Addiction and of N -Acetylcysteine as a Potential Pharmacotherapy

JAMA Psychiatry, 2013

The prevalence and impact of drug addiction on society are staggering. The abuse of alcohol, tobacco, and illicit drugs accounts for approximately 10% of the global burden of disease, and for the United States, it is estimated that substance use disorders affect 20.4 million individuals. 1 Despite the deleterious economic and social consequences of drug use, approved medications to treat substance use disorders are few or absent depending on the drug. We and others have explored the possibility that dysregulation in prefrontal and allocortical (amygdala and hippocampus) glutamatergic inputs to the basal ganglia may be a mechanism responsible for relapse that is shared between classes of addictive drugs, as well as other disorders characterized by maladaptive compulsive behavior. Herein, we describe the benchto-bedside chronology of preclinical discovery and clinical trials that led to the cysteine prodrug N-acetylcysteine being evaluated for the treatment of substance abuse and compulsive disorders. Drug addiction is a chronic brain disorder characterized by compulsive drug use that occurs at the expense of other biologically adaptive activities. The transition from casual to compulsive drug use and the enduring propensity to relapse is maintained by longlasting neuroadaptations in specific brain circuits. For example, it is well established that all drugs of abuse enhance dopamine neurotransmission to reinforce and establish drug-seeking behavior. Although less thoroughly studied, we and others have shown that the enduring vulnerability to relapse to drug use involves the recruitment of glutamatergic projections to the ventral striatum, in particular the nucleus accumbens, and is associated with enduring changes in glutamatergic synaptic transmission. Glutamatergic inputs from the amygdala, hippocampus, and prefrontal cortex to the accumbens regulate adaptive behavioral responses by integrating environmental stimuli with memories of related experiences. 2 Thus, by producing enduring changes in glutamatergic synapses in the accumbens, longterm use of addictive drugs impairs the ability of an individual to inhibit drug seeking and use, ultimately producing the persistent relapsing disorder that characterizes drug addiction. Animal models of drug addiction have shown that drug seeking is associated with increased glutamate release from prefrontal projections into the nucleus accumbens. When large amounts of glutamate are released, the excess spills out of the synaptic cleft and activates extrasynaptic glutamate receptors (Figure). Demonstrating spillover of synaptically released glutamate in animals trained to self-administer cocaine, heroin, nicotine, or alcohol was an important indication that alterations in glutamatergic synapses might be re