A single extinction-based treatment with N-Acetylcysteine produces long-term reduction in cocaine relapse

Cocaine addiction is characterized by high relapse rates associated with glutamate dysregulation, presenting significant challenges for long-term treatment. N-acetylcysteine (NAC) has shown promise in preventing drug relapse by normalizing glutamate function, potentially mediated by glutamate 2/3 (mGlu2/3) receptor activation. This study investigated the therapeutic potential of NAC in reducing cocaine-seeking behavior using the self-administration model. After establishing stable cocaine self-administration and a 7-day abstinence period, rats received a single dose of NAC (100 mg/kg, i.p.) 30 min before the first extinction training session. NAC significantly reduced cocaine-seeking behavior on the first day of extinction but not in subsequent extinction sessions. Following extinction, tests for cue-induced reinstatement and spontaneous recovery were conducted. Results showed that NAC administration on the first day of extinction effectively reduced cocaine-seeking during the reinstatement test, with effects lasting at least 28 days. The mGlu2/3 antagonist LY341495 (1 mg/kg) fully blocked this enduring suppression of reinstatement without altering the immediate decrease in drug-seeking observed on the first day of extinction. Additionally, NAC administration on the initial extinction day also reduced context-induced reinstatement of cocaine-seeking behavior. These results indicate that NAC exerts its anti-relapse effects via mGlu2/3 receptors. A single NAC treatment combined with extinction training can produce lasting suppression of relapse, highlighting its therapeutic promise for addiction treatment.