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 self-administration 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 + cocaine-primed, and context-induced relapse. Chronic NAC administration blunted cocaine seeking under multiple experimental protocols. Specifically, NAC attenuated responding during cue and cue + cocaine-primed reinstatement tests after extinction and context, cue, and cue + 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.

Fig. 1.

Experiment 1: 60 mg/kg NAC during extinction. A, time course for experiment 1. NAC (60 mg/kg) treatment occurred during daily extinction sessions and on cue-induced and cue + cocaine-primed reinstatement test days. Rats were retested after 2 weeks of abstinence without NAC. B, active lever presses during the last 3 days of self-administration. C, lever responding over the 12 days of extinction. D, reinstatement of cocaine-seeking by cues or cues + cocaine. *, reduced responding by NAC treatment relative to saline treatment; p < 0.05. E, cocaine seeking at 2 weeks after discontinuation of NAC treatment. Sal, saline; VEH, vehicle.

Fig. 2.

Experiment 2: 100 mg/kg NAC during extinction. A, time course for experiment 2. NAC (100 mg/kg) treatment occurred during daily extinction sessions and on cue and cue + cocaine-primed reinstatement testing. Rats were retested after 2 weeks of abstinence without NAC. B, active lever presses during the last 3 days of self-administration. C, lever responding over the 12 days of extinction (main effect of group, p < 0.05). D, reinstatement of cocaine seeking by cues or cues + cocaine. *, reduced responding by NAC treatment relative to saline treatment; p < 0.05. E, cocaine seeking at 2 weeks after discontinuation of NAC treatment. *, reduced responding by NAC treatment relative to saline treatment; p < 0.05. Sal, saline; VEH, vehicle.

Fig. 3.

Experiment 3: 60 mg/kg NAC during abstinence. A, time course for experiment 3. NAC (60 mg/kg) treatment occurred daily during abstinence but not on tests or during extinction. Rats were tested for context relapse and went through subsequent extinction and reinstatement testing. B, active lever presses during the last 3 days of self-administration. C, relapse to the cocaine context after abstinence. D, lever responding over the 11 days of extinction. *, increased responding by NAC relative to saline. E, reinstatement of cocaine seeking by cues or cocaine. Sal, saline; VEH, vehicle.

Fig. 4.

Experiment 4: 100 mg/kg NAC during abstinence. A, time course for experiment 4. NAC (100 mg/kg) treatment occurred daily during abstinence, but not on tests or during extinction. Rats were tested for context relapse and went through subsequent extinction and reinstatement testing. B, active lever presses during the last 3 days of self-administration. C, relapse to the cocaine context after abstinence. *, reduced responding by NAC treatment relative to saline treatment; p < 0.05. D, lever responding over the 11 days of extinction. E, reinstatement of cocaine seeking by cues or cocaine. Sal, saline; VEH, vehicle.

Fig. 5.

Experiment 5: 100 mg/kg NAC during abstinence. A, time course for experiment 5. NAC (100 mg/kg) treatment occurred daily during abstinence and on cue and cue + cocaine-primed reinstatement testing. Rats were retested after 2 weeks of abstinence without NAC. B, relapse of cocaine seeking by cues or cues + cocaine. *, reduced responding by NAC treatment relative to saline treatment; p < 0.05. C, cocaine seeking at 2 weeks after discontinuation of NAC treatment. *, reduced responding by NAC treatment relative to saline treatment; p < 0.05. Sal, saline; VEH, vehicle.