Reward Circuit Adaptations After Chronic Antipsychotic Treatment Confer Addiction Vulnerability

ObjectiveAntipsychotics are widely used chronically to treat several psychiatric conditions and off-label indications, but their clinical utility is often accompanied by motor and/or metabolic side effects. Antipsychotics can also alter the brains reward circuitry, and we recently showed that upon abrupt discontinuation, chronic treatment with the first-generation antipsychotic haloperidol increases cocaine relapse in a rodent model of i.v. cocaine self-administration. Here, we examined whether chronic treatment with second-generation antipsychotics was also associated with increased addiction vulnerability in rodents and humans, and sought to further characterize the cellular substrate linking antipsychotic exposure to substance use disorder (SUD). MethodsAdult rats received subcutaneous infusion of risperidone, olanzapine, or vehicle for 14 days. Rats were then trained to self-administer i.v. cocaine or oral sucrose pellets for 10 days and active lever presses were paired with compound cue exposure. After a period of extinction training, reward seeking was reinstated by restoration of cues to active lever pressing for 20 minutes. To enable quantification of dendritic spine morphology and manipulation of MSNs during relapse, viral approaches were used to label D1- or D2-MSNs in the nucleus accumbens core (NAcore), a region that encodes reward-related responses and regulates symptoms associated with addiction and other psychiatric disorders, including schizophrenia. To assess the clinical relationship between chronic antipsychotic use and SUD, we conducted a systematic review and meta-analysis of studies identified through PubMed, CENTRAL, Scopus, and Embase that examined the effects of antipsychotic treatment on addictive substance use or craving in patients with SUD. ResultsIn rats, chronic risperidone or olanzapine treatment delayed extinction learning and increased cue-induced cocaine seeking, but did not alter seeking of the natural reward sucrose or its extinction. Cued relapse increased spine head diameter in NAcore D2-MSNs, but not D1-MSNs after antipsychotic treatment relative to vehicle-treated controls. Chemogenetic inhibition of D2-MSNs reversed addiction vulnerability conferred by antipsychotic treatment. In patients whose SUDs were treated with antipsychotics, duration of treatment (>4 months) strongly predicted addictive substance use or craving independent of antipsychotic type (first- vs. second-generation) or misused substance (psychostimulant, opioid, alcohol, or cannabis). ConclusionsChronic antipsychotic treatment, regardless of drug class, was associated with increased vulnerability to addictive substance use and relapse-like behavior in a rat model, and was linked to potentiation of D2-MSNs in the ventral striatum. In humans, systematic review and meta-analytic findings supported this pattern in patients maintained on antipsychotic treatment.