Repeated N-Acetyl Cysteine Reduces Cocaine Seeking in Rodents and Craving in Cocaine-Dependent Humans

Author(s): Shelley L Amen, Linda B Piacentine, Muhammad E Ahmad, Shi-Jiang Li, John R Mantsch, Robert C Risinger and David A Baker


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 xc– 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=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=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.


by David Baker
The key findings of this manuscript are that repeated administration of N-acetylcysteine, which is used to increase cystine-glutamate exchange from system xc-, reduces cocaine-induced drug seeking in rodents and craving in cocaine-dependent humans.  These data further support efforts to normalize glutamate homeostasis as a novel approach to treating drug addiction and establish system xc- as an effective target in these efforts.  Interestingly, repeated N-acetylcysteine failed to alter cocaine reinforcement in rodents or measures of euphoria in cocaine-dependent humans thereby posing an intriguing question.  Specifically, is the value of a medication for addiction significantly diminished if the euphoric properties of the abused drug persist in a manner that supports recreational drug use even if compulsive drug use is at least partially abated?  Importantly, the design of the study enabled a direct comparison of the impact of N-acetylcysteine between rodents and humans, thereby providing a unique dataset for the ongoing discussion of the predictive validity of the self-administration/reinstatement paradigm, which has arisen in part because of apparent false positives in which drugs that block reinstatement fail to produce a positive effect in clinical trials.  However, the inconsistencies between preclinical and clinical studies may not be due to the validity of the reinstatement paradigm but instead to dissimilar measures and manipulations in each study.  The typical reinstatement study examines the capacity of an acute administration of a potential medication to disrupt an acute increase in drug seeking produced by a stimulus that can cause relapse in humans (e.g., drug prime, drug cues or context, or stress) whereas the typical clinical trial assesses the capacity of chronic administration of a potential medication to reduce drug use.  Thus, key assumptions being made are that a) the effectiveness of a compound is not diminished following repeated administration, b) reinstatement models aspect of addiction, such as craving, c) that the phenomena being modeled, such as craving, are a primary driver of continued drug use.  In our study, we compared the effect of repeated N-acetylcysteine on evoked changes in drug seeking or craving, thereby more similarly designing each arm of the study to better enable comparisons across species.  In the event that our data are replicated, but N-acetylcysteine fails to produce a positive outcome in clinical studies, it could indicate that the reinstatement paradigm has predictive validity for changes in craving, but that these changes are insufficient to curb drug use.

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