Comparison of antidepressant-like and abuse-related effects of phencyclidine in rats.

Abstract

Preclinical Research N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine, have emerged as novel candidate treatments for major depressive disorder, but abuse potential of these agents is a concern. The NMDA antagonist phencyclidine has known abuse liability but undefined efficacy as an antidepressant. To further evaluate the relationship between antidepressant-like and abuse-related effects of NMDA antagonists, this study evaluated the effects of phencyclidine (1.0-10.0 mg/kg) in male Sprague-Dawley rats responding under two procedures that have been used to assess antidepressant-like effects (differential-reinforcement-of-low-rate [DRL] 72 s schedule of food reinforcement; n = 9) and abuse-related drug effects (intracranial self-stimulation [ICSS]; n = 6). Under the DRL 72 s schedule, phencyclidine (10.0 mg/kg) increased reinforcers and decreased responses without shifting the peak location of the interresponse time (IRT) distribution. Ketamine (10.0 mg/kg) also increased reinforcers and decreased responses, but unlike phencyclidine, it produced a rightward shift in the peak location of the IRT distribution. The 10.0 mg/kg phencyclidine dose that decreased DRL 72 s responding also decreased rates of ICSS for 50 min after its administration; however, abuse-related ICSS facilitation was observed at later times (100-300 min) or after a lower phencyclidine dose (3.2 mg/kg). These results suggest that phencyclidine produces weaker antidepressant-like effects, but stronger abuse-related effects than ketamine in these procedures.