Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans

Abstract

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=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.

Figure 1

Participants underwent phone and clinical interview/laboratory screening (S) before study enrollment (E). After 1 to 8 weeks, participants underwent a run-up procedure (R) to determine the safety of delivering cocaine (20 mg per 70 kg IV over 60 s). Afterwards, participants remained inpatient for 1 to 2 separate 4-day/3-night stays, each with one blinded, oral study medication: treatment A (oral N-acetyl cysteine; 400 or 800 mg TID) or B (oral baclofen; 20 mg TID). During each inpatient visit, the participant underwent a 1-h test session before and after drug treatment (pretest and posttest, respectively) while receiving a total of nine doses of the test medication during the 3 days between the two tests. Participants were discharged home on day 4, with some returning after a 7- to 14-day treatment washout period (W) for the second treatment arm of the study. After 12 to 16 days of the end of the final arm, participants returned for a discharge interview (DC) before study termination.

Figure 2

Daily N-acetyl cysteine does not alter the amount of cocaine self-administered by rats. Data depict the mean±SEM number of infusions across 12 maintenance self-administration sessions. Rats received N-acetyl cysteine (0 or 60 mg/kg, IP) 60 min before each session of cocaine self-administration (0.5 mg/kg, IV/infusion; 2 h/day; N=7/group).

Figure 3

Daily N-acetyl cysteine does not alter cocaine-induced rush (a) or high (b) in cocaine-dependent human participants. Data depict a change in self-reports (mean±SEM) of rush and high from baseline values collected immediately before values obtained during exposure to a neutral video and cocaine video, or following a cocaine injection (20 mg/70 kg/60 s, IV). Measures of rush and high were obtained before and following daily baclofen (20 mg; TID; N=4) or N-acetyl cysteine (400 or 800 mg; TID; N=4) treatment.

Figure 4

Daily N-acetyl cysteine decreases cocaine-induced reinstatement in rodents. Data depict the mean (±SEM) number of lever presses over during the last extinction test, or during two reinstatement tests. Rats self-administered cocaine (0.5 mg/kg/200 μl IV; 2-h/day; N=10–12/group) over 12 daily sessions. After 7 days of the last self-administration session, rats underwent daily extinction training in the absence of any drug treatment. This was followed by a test for cocaine-induced (10 mg/kg, IP) reinstatement. The day after the first reinstatement test, rats received seven daily injections of saline or N-acetyl cysteine (60 mg/kg, IP). The day after the seventh and final injection of saline or N-acetyl cysteine, rats underwent a second test for cocaine-induced reinstatement. ^#A significant difference from the first reinstatement test; t-test, p<0.05. ^*A significant difference from extinction responding, p<0.05.

Figure 5

N-acetyl cysteine reduces craving reported after a cocaine injection by human cocaine-dependent participants. Data depict a change in self-reports (mean±SEM) of craving from baseline values collected immediately before values obtained during exposure to a neutral video and cocaine video, or following a cocaine injection (20 mg/70 kg/60 s, IV). Measures of craving were obtained before and after daily baclofen (20 mg; TID; N=4) or N-acetyl cysteine (400 or 800 mg; TID; N=4) treatment. ^*A significant difference from craving reported following a cocaine injection on test day 1 (eg, pre-baclofen or N-acetyl cysteine treatment), p<0.05, t-test.