Chronic N-Acetylcysteine during Abstinence or Extinction after Cocaine Self-Administration Produces Enduring Reductions in Drug Seeking

Abstract

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

“…Another advantage of NAC as a therapy for addiction is robust efficacy independent of when the drug is administered. NAC treatment is effective in inhibiting drug seeking if given daily during selfadministration, injected for 5 days during withdrawal many weeks before a reinstatement trial, or administered acutely just prior to reinstatement trial (Madayag et al, 2007;Reichel et al, 2011;Murray et al, 2012a). In rodent models, NAC treatment also facilitates extinction learning and enhances the rate of extinction of responding for both cocaine and heroin Murray et al, 2012a).…”

Morphine Induces Redox-Based Changes in Global DNA Methylation and Retrotransposon Transcription by Inhibition of Excitatory Amino Acid Transporter Type 3–Mediated Cysteine Uptake

“…Use of N-acetylcysteine in symptomatic treatment of alcohol (Ferreira Seiva et al, 2009), cocaine dependence (Mardikian et al, 2007), and withdrawal (Reichel et al, 2011) presents efforts in exploiting this pathway. EAAT3 itself may provide a potential site for pharmacologic intervention, along with factors/systems which regulate its activity.…”

N-Acetylcysteine as a Treatment for Addiction

“…There was no effect of the lower 60 mg/kg dose of NAC on extinction responding. However, there was a significant enhancement of extinction (i.e., less active lever pressing) when rats were treated daily with 100 mg/kg NAC Reichel et al, 2011). This effect was also found during extinction of heroin self-administration for which daily administration of 100 mg/kg NAC resulted in enhanced extinction rate (Zhou & Kalivas, 2008).…”

“…However, when NAC (100 mg/kg) was administered during extinction following either cocaine or heroin self administration, there was a significant reduction in both cue-and cue+drug-or drug-induced reinstatement. These results suggest that, compared to a conditioned stimulus, a higher treatment dose was necessary to disrupt the ability of an unconditioned drug stimulus+drug-associated CS compound to reinstate drugtaking behavior Reichel et al, 2011;Zhou & Kalivas, 2008). Notably, these effects on reinstatement lasted from two weeks Reichel et al, 2011) to 40 days (Zhou & Kalivas, 2008) following the last 100 mg/kg NAC treatment, indicating a long-term restoration of glutamate homeostasis in the NAcC brought about by the re-regulation induced by chronic NAC exposure .…”

“…These results suggest that, compared to a conditioned stimulus, a higher treatment dose was necessary to disrupt the ability of an unconditioned drug stimulus+drug-associated CS compound to reinstate drugtaking behavior Reichel et al, 2011;Zhou & Kalivas, 2008). Notably, these effects on reinstatement lasted from two weeks Reichel et al, 2011) to 40 days (Zhou & Kalivas, 2008) following the last 100 mg/kg NAC treatment, indicating a long-term restoration of glutamate homeostasis in the NAcC brought about by the re-regulation induced by chronic NAC exposure . At the neurophysiological level, rats trained to self-administer cocaine that received saline (rather than NAC) during extinction showed reduced extrasynaptic glutamate levels in the NAcC compared to saline-yoked controls.…”