N‐Acetylcysteine reduces early‐and late‐stage cocaine seeking without affecting cocaine taking in rats (original) (raw)
Related papers
The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine
Biological Psychiatry
Background-Relapse to cocaine-seeking has been linked with low glutamate in the nucleus accumbens core (NAcore) causing potentiation of synaptic glutamate transmission from prefrontal cortex (PFC) afferents. Systemic N-acetylcysteine (NAC) has been shown to restore glutamate homeostasis, reduce relapse to cocaine-seeking and depotentiate PFC-NAcore synapses. Here we examine the effects of NAC applied directly to the NAcore on relapse and neurotransmission in PFC-NAcore synapses, as well as the involvement of the metabotropic glutamate receptors (mGluRs) mGluR2/3 and mGluR5.
Journal of Pharmacology and Experimental Therapeutics, 2011
The cysteine prodrug N-acetylcysteine (NAC) has been shown to reduce reinstatement of cocaine seeking by normalization of glutamatergic tone. However, enduring inhibition of cocaine seeking produced by NAC has not been explored under different withdrawal conditions. Thus, the present study determined whether chronic NAC administered during daily extinction training or daily abstinence after withdrawal from cocaine selfadministration would reduce cocaine seeking. Rats self-administered intravenous cocaine during daily 2-h sessions for 12 days, followed by daily extinction or abstinence sessions. During this period, rats received daily injections of saline or NAC (60 or 100 mg/kg). Subsequently, rats were tested for cocaine seeking via conditioned cue, cue ϩ cocaine-primed, and con-text-induced relapse. Chronic NAC administration blunted cocaine seeking under multiple experimental protocols. Specifically, NAC attenuated responding during cue and cue ϩ cocaine-primed reinstatement tests after extinction and context, cue, and cue ϩ cocaine relapse tests after abstinence. Protection from relapse by NAC persisted well after treatment was discontinued, particularly when the high dose was combined with extinction trials. The finding that NAC reduced cocaine seeking after drug treatment was discontinued has important implications for the development of effective antirelapse medications. These results support recent preclinical and clinical findings that NAC may serve as an effective treatment for inhibiting relapse in cocaine addicts.
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
N-acetylcysteine Facilitates Self-Imposed Abstinence After Escalation of Cocaine Intake
Biological Psychiatry, 2016
BACKGROUND: N-acetylcysteine (NAC) has been suggested to prevent relapse to cocaine seeking. However, the psychological processes underlying its potential therapeutic benefit remain largely unknown. METHODS: We investigated the hallmark features of addiction that were influenced by chronic NAC treatment in rats given extended access to cocaine: escalation, motivation, self-imposed abstinence in the face of punishment, or propensity to relapse. For this, Sprague Dawley rats were given access either to 1 hour (short access) or 6 hours (long access [LgA]) self-administration (SA) sessions until LgA rats displayed a robust escalation. Rats then received daily saline or NAC (60 mg/kg, intraperitoneal) treatment and were tested under a progressive ratio and several consecutive sessions in which lever presses were punished by mild electric foot shocks. RESULTS: NAC increased the sensitivity to punishment in LgA rats only, thereby promoting abstinence. Following the cessation of punishment, NAC-treated LgA rats failed to recover fully their prepunishment cocaine intake levels and resumed cocaine SA at a lower rate than short access and vehicle-treated LgA rats. However, NAC altered neither the escalation of SA nor the motivation for cocaine. At the neurobiological level, NAC reversed cocaineinduced decreases in the glutamate type 1 transporter observed in both the nucleus accumbens and the dorsolateral striatum. NAC also increased the expression of Zif268 in the nucleus accumbens and dorsolateral striatum of LgA rats. CONCLUSIONS: Our results indicate that NAC contributes to the restoration of control over cocaine SA following adverse consequences, an effect associated with plasticity mechanisms in both the ventral and dorsolateral striatum.
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
Effects of Repeated Cocaine Exposure on Habit Learning and Reversal by N-Acetylcysteine
Neuropsychopharmacology, 2014
Exposure to drugs of abuse can result in a loss of control over both drug-and nondrug-related actions by accelerating the transition from goal-directed to habitual control, an effect argued to reflect changes in glutamate homeostasis. Here we examined whether exposure to cocaine accelerates habit learning and used in vitro electrophysiology to investigate its effects on measures of synaptic plasticity in the dorsomedial (DMS) and dorsolateral (DLS) striatum, areas critical for actions and habits, respectively. We then administered N-acetylcysteine (NAC) in an attempt to normalize glutamate homeostasis and hence reverse the cellular and behavioral effects of cocaine exposure. Rats received daily injections of cocaine (30 mg/kg) for 6 days and were then trained to lever press for a food reward. We used outcome devaluation and whole-cell patch-clamp electrophysiology to assess the behavioral and cellular effects of cocaine exposure. We then examined the ability of NAC to reverse the effects of cocaine exposure on these measures. Cocaine treatment produced a deficit in goal-directed action, as assessed by outcome devaluation, and increased the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) in the DMS but not in the DLS. Importantly, NAC treatment both normalized EPSC frequency and promoted goal-directed control in cocaine-treated rats. The promotion of goal-directed control has the potential to improve treatment outcomes in human cocaine addicts.
…, 2010
Addiction is a chronic relapsing disorder hypothesized to be produced by drug-induced plasticity that renders individuals vulnerable to craving-inducing stimuli such as re-exposure to the drug of abuse. Drug-induced plasticity that may result in the addiction phenotype includes increased excitatory signaling within corticostriatal pathways that correlates with craving in humans and is necessary for reinstatement in rodents. Reduced cystine-glutamate exchange by system x c -appears to contribute to heightened excitatory signaling within the striatum, thereby posing this as a novel target in the treatment of addiction. In the present report, we examined the impact of repeated N-acetyl cysteine, which is commonly used to activate cystine-glutamate exchange, on reinstatement in rodents in a preclinical study and on craving in cocaine-dependent humans in a preliminary, proof-of-concept clinical experiment. Interestingly, repeated administration (7 days) of N-acetyl cysteine (60 mg/kg, IP) produced a significant reduction in cocaine (10 mg/kg, IP)-induced reinstatement, even though rats (N ¼ 10-12/group) were tested 24 h after the last administration of N-acetyl cysteine. The reduction in behavior despite the absence of the N-acetyl cysteine indicates that repeated N-acetyl cysteine may have altered drug-induced plasticity that underlies drug-seeking behavior. In parallel, our preliminary clinical data indicate that repeated administration (4 days) of N-acetyl cysteine (1200-2400 mg/day) to cocaine-dependent human subjects (N ¼ 4 per group) produced a significant reduction in craving following an experimenter-delivered IV injection of cocaine (20 mg/70 kg/60 s). Collectively, these data demonstrate that N-acetyl cysteine diminishes the motivational qualities of a cocaine challenge injection possibly by altering pathogenic drug-induced plasticity.
Is cocaine desire reduced by N-acetylcysteine?
The American journal of psychiatry, 2007
Animal models suggest that N-acetylcysteine inhibits cocaine-seeking. The present pilot study evaluated whether N-acetylcysteine would suppress reactivity to cocaine-related cues in cocaine-dependent humans. In this double-blind, placebo-controlled trial, 15 participants received N-acetylcysteine or placebo during a 3-day hospitalization. Participants were crossed over to receive the opposite condition on a second, identical 3-day stay occurring 4 days later. During each hospital stay, participants completed a cue-reactivity procedure that involved collecting psychophysical and subjective data in response to slides depicting cocaine and cocaine use. While taking N-acetylcysteine, participants reported less desire to use and less interest in response to cocaine slides and watched cocaine slides for less time. The inhibition of cocaine cue reactivity is consistent with existing preclinical data and supports the use of N-acetylcysteine as a treatment for cocaine dependence.