N-Acetylcysteine treatment during acute stress prevents stress-induced augmentation of addictive drug use and relapse

Converging epidemiological studies show that a life-threatening event increases the incidence of posttraumatic stress disorder (PTSD), which carries 30% to 50% comorbidity with substance use disorders (SUDs). Such comorbidity results in greater drug use and poorer treatment outcomes. There is overlap between the enduring synaptic neuroadaptations produced in nucleus accumbens core (NAcore) by acute restraint stress and cocaine self-administration. Because of these coincident neuroadaptations, we hypothesized that an odor paired with acute restraint stress would reinstate drug seeking and chose two mechanistically distinct drugs of abuse to test this hypothesis: alcohol and cocaine. Rats were trained to self-administer either drug beginning 3 weeks after odor pairing with acute stress or sham, and acute restraint stress increased alcohol consumption. Following context extinction training, the stress-paired odor reinstated both alcohol and cocaine seeking, while an unpaired odor had no effect. N-Acetylcysteine (NAC) restores drug and stress-induced reductions in glial glutamate transporter-1 and has proven effective at reducing cue-induced reinstatement of drug seeking. We administered NAC for 5 days prior to reinstatement testing and abolished the capacity of the stress-paired odor to increase alcohol and cocaine seeking. Importantly, daily NAC given during or just following experiencing acute restraint stress also prevented the capacity of stress-paired odors to reinstate alcohol and cocaine seeking and prevented stress-induced deficits in behavioral flexibility. These data support using daily NAC treatment during or immediately after experiencing a strong acute stress to prevent subsequent conditioned stress responding, in particular relapse and cognitive deficits induced by stress-conditioned stimuli.