N -Acetylcysteine reduces cocaine-cue attentional bias and differentially alters cocaine self-administration based on dosing order

Abstract

Background Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans. Methods The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400 mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60 mg). Fourteen individuals (N = 14) who met criteria for cocaine abuse or dependence completed this within-subjects, double-blind, crossover-design study. Results Cocaine-cue attentional bias was greatest following administration of 0 mg cocaine during placebo maintenance, and was attenuated by n-acetylcysteine. Cocaine maintained responding during placebo and n-acetylcysteine maintenance, but the reinforcing effects of cocaine were significantly attenuated across both maintenance conditions in participants maintained on n-acetylcysteine first compared to participants maintained on placebo first. Conclusions These results collectively suggest that a reduction in the incentive salience of cocaine-related stimuli during n-acetylcysteine maintenance may be accompanied by reductions in cocaine self-administration. These results are in agreement with, and link, prior preclinical and clinical trial results suggesting that n-acetylcysteine might be useful for preventing cocaine relapse by attenuating the incentive salience of cocaine cues.

Influence of n-acetylcysteine maintenance on the pharmacodynamic effects of oral ethanol

“…n-Acetylcysteine maintenance generally did not affect physiological outcomes, with breath alcohol concentrations and blood pressure readings being similar across dose conditions. Although we observed increases in heart rate during n -acetylcysteine maintenance, a number of other studies have not observed this effect in populations without alcohol use disorder (e.g., Bolin et al, 2017 ; Leelarungrayub et al, 2011 ; Hirai et al, 2017 ), so future work is needed to confirm how n -acetylcysteine affects heart rate in individuals with alcohol use disorder.…”

“…The n -acetylcysteine maintenance period was selected based on our previous work with n -acetylcysteine ( Bolin et al, 2017 ), showing that a similar n -acetylcysteine regimen reduced cocaine self-administration in a maintenance-order dependent manner and reduced cocaine attentional bias. We also selected the maintenance period based on research published by other laboratories ( Amen et al, 2011 ).…”

The effect of N-acetylcysteine and working memory training on cocaine use, craving and inhibition in regular cocaine users: correspondence of lab assessments and Ecological Momentary Assessment

“…This has been found for several cognitive functions (Skvarc et al, 2017), but whether NAC also has an effect on cognitive control in SUDs remains to be investigated. Although studies exist on the effect of NAC on induced craving (in which WM is used as a distractor; Amen et al, 2011) and the positive effect of NAC on attentional bias (Bolin et al, 2017), in our study we specifically examined the effect of NAC to improve cognitive control in SUDs.…”

The Persistent Challenge of Developing Addiction Pharmacotherapies

“…Clinical trials demonstrate that NAC attenuated cocaine use and decreased desire to use cocaine (LaRowe et al 2007;Mardikian et al 2007). Recent clinical trials also support the ability of NAC to reduce incentive salience for cocaine cues (Levi et al 2017) and delay relapse in cocaine-abstinent subjects (LaRowe et al 2013), suggesting that NAC may be therapeutically beneficial in maintaining abstinence and/or preventing relapse. Another interesting strategy is the development of cocaine vaccines.…”