MDPV‐induced Insensitivity to Cataleptic Effects of Haloperidol: A Model of Psychostimulant‐induced Psychosis?

Abstract

Repeated exposure to psychostimulants can produce persistent changes in behavior and neurochemistry, including pro‐psychotic effects. Behavioral responses associated with psychostimulant‐induced psychosis resemble the positive symptoms of schizophrenia, but methods used to assess psychostimulant‐induced psychosis in rodents are sometimes procedurally tedious or require specialized equipment. The purpose of the present experiments was to develop a high‐throughput procedure for assessing the pro‐psychotic effects of repeated exposure to the synthetic cathinone 3,4‐methylenedioxypyrovalerone (MDPV), a common constituent of illicit “bath salts” products. MDPV has been reported to induce psychosis in recreational users, and its neuropharmacological actions on brain dopamine systems are reasonably well understood. It was hypothesized that pro‐psychotic effects of repeated MDPV exposure would decrease sensitivity to the anti‐psychotic effects of the dopamine D2 receptor antagonist, haloperidol, in mice. Sensitivity to haloperidol was evaluated by assessing cataleptic effects across a range of doses following drug or saline exposure. In experiment one, a cumulative‐dosing procedure was conducted to identify pharmacologically‐active doses of haloperidol (0.1 – 10 mg/kg) in male NIH Swiss Webster mice. In experiment two, a group of mice that had a 10 day, oral self‐administration history of 0.3 mg/ml MDPV was compared to a water control group at approximately 3 weeks following the last day of the self‐administration sessions. The results of experiment two revealed that the MDPV group was less sensitive to haloperidol's cataleptic effects compared to the control group. In experiment three, one group of mice received four intraperitoneal injections of 3 mg/kg MDPV spaced two hours apart on a single day (“binge session”) and another group received saline injections on the same schedule. Haloperidol‐induced catalepsy was repeatedly assessed at 72 hr, 1, 2, and 4 weeks following the binge session. The results of experiment three revealed that both groups displayed successively greater sensitivity to haloperidol's cataleptic effects across the four time points measured post‐binge. In addition, MDPV‐treated mice displayed the greatest reduction in sensitivity to haloperidol's effects at 2 weeks post‐binge. Finally, in experiment four, mice received eight injections (ip) of 3 mg/kg MDPV once daily, every other day, for 15 consecutive days. Haloperidol‐induced catalepsy was assessed two weeks following the final injection of MDPV. Results of this experimented will be presented. Overall, these pilot experiments indicate that repeated MDPV exposure produces a reduced sensitivity to the cataleptic effects of haloperidol. Because haloperidol's clinical response in patients with schizophrenia is correlated with increased D2 receptor occupancy, we believe that this model may have predictive validity in measuring psychostimulant‐induced psychosis.Support or Funding InformationThese studies were funded by the National Institute on Drug Abuse (NIDA) R01 DA039195, and in part by an NIGMS IDeA Program award (GM110702) and by the UAMS Translational Research Institute (RR029884).