Comparison of Antidepressant‐Like and Abuse‐Related Effects of Phencyclidine in Rats

Abstract

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.

Temporally dissociable effects of ketamine on neuronal discharge and gamma oscillations in rat thalamo-cortical networks

“…Collectively, these observations suggest an involvement of thalamo-cortical pathways in the action of ketamine, as previously observed for phencyclidine (PCP), another non-competitive NMDA-R antagonist. PCP has also been shown to elicit weak antidepressant-like effects in one rodent study (Hillhouse et al, 2014). In anesthetized rats, PCP inhibits GABAergic neurons from the reticular nucleus of the thalamus (RtN) (Troyano-Rodriguez et al, 2014), which tonically inhibits the rest of the thalamic nuclei.…”

Molecular profile of dissociative drug ketamine in relation to its rapid antidepressant action

“…The complex pharmacological profile of ketamine makes it difficult to postulate a specific mechanism of its rapid antidepressant effect. The comparison with other NMDA receptor antagonists does not provide clear indication of the possible mechanism of action [ 7 , 8 ]. Phencyclidine (PCP) induces cognitive disruption and psychotic-spectrum reactions but, unlike ketamine, was not observed to have antidepressant effects in humans.…”

Effects of the noncompetitive N-methyl-D-aspartate receptor antagonist ketamine on visual signal detection performance in rats

“…There were two main findings. First, ketamine (10.0-18.0 mg/kg) decreased signal detection performance at doses that have been shown to produce antidepressant-like effects in rats (Hillhouse et al, 2014a,b; Koike et al, 2013; Reus et al, 2011; Zhou et al, 2014). The effects of ketamine in the present study are consistent with the effects of the noncompetitive NMDA receptor antagonist MK-801, which also produces a decrease in percent hit and correct rejection accuracy and increases in response latency and trial omissions (Rezvani et al, 2009).…”

“…Doses and pretreatment times were based on previous studies in the literature (Hillhouse and Porter, 2014; Hillhouse et al, 2014a,b; Koike et al, 2013; Páleníček et al, 2011). …”