An evaluation of N-acetylcysteine in a sequential oxycodone and cocaine rat self-administration model

Polysubstance use, particularly opioid-stimulant co-use, is a public health concern associated with higher overdose risk and poor treatment outcomes. Preclinical evidence suggests that oxycodone withdrawal increases cocaine consumption and disrupts nucleus accumbens glutamate homeostasis. N-acetylcysteine (NAC), a cysteine prodrug that restores glutamate homeostasis, has shown preclinical promise in reducing drug seeking in single substance seeking models. However, no studies have evaluated the efficacy of NAC in reducing behavioral outcomes, including self-administration, following opioid-stimulant polysubstance use. Here, we evaluated NAC as a pharmacotherapeutic for oxycodone-cocaine sequential use using our previously established rat intravenous self-administration model, which utilized an A-B-A-B design. We previously found that rats increase cocaine consumption during oxycodone withdrawal. Thus, here, we tested if NAC could reduce this effect and reduce oxycodone self-administration. Male and female rats first underwent oxycodone or food self-administration acquisition, followed by cocaine self-administration in Phase 2. Rats were subsequently treated with NAC (100 mg/kg) or vehicle during Phase 3, where the reinforcer switched back to the one presented in Phase 1. In Phase 4, we assessed cocaine self-administration and somatic signs during an oxycodone-free period. NAC treatment did not alter oxycodone or cocaine consumption, response discrimination, or somatic signs during drug onboard and drug-free periods. Cocaine consumption was inversely associated with somatic signs at early but not more protracted timepoints independent of NAC treatment. While NAC did not attenuate cocaine or oxycodone intake-related behaviors in our sequential use model, these results underscore the need for expanded polysubstance use pharmacotherapeutic and model development. (PsycInfo Database Record (c) 2026 APA, all rights reserved).