The selective glycine antagonist gavestinel lacks phencyclidine-like behavioral effects

Abstract

Gavestinel [GV150526A; ( E)-3[(phenylcarbamoil)ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt] is a selective antagonist at the strychnine-insensitive glycine site of the -methyl-D-aspartate (NMDA) receptor. It was tested for its ability to substitute for phencyclidine (PCP) in rats and rhesus monkeys trained to discriminate PCP from saline, under a two-lever fixed-ratio (FR) food reinforcement schedule, and for its ability to maintain responding in rhesus monkeys trained to self-administer PCP under a FR reinforcement schedule. No PCP-lever responding was observed after gavestinel (1-56 mg/kg i.p.) administration to rats discriminating PCP (2.0 mg/kg i.p.) from saline. The highest dose of gavestinel (100 mg/kg i.p.) tested eliminated responding. Likewise, no PCP-lever responding was observed after gavestinel (1-30 mg/kg s.c.) administration to rhesus monkeys discriminating PCP (0.08 or 0.1 mg/kg i.m.) from saline; the highest dose of gavestinel (30 mg/kg s.c.) tested reduced response rates to approximately 50% of those observed after its vehicle ( -cyclodextrin in 0.9% saline). Gavestinel (0.1-1 mg/kg per i.v. infusion) was not self-administered by rhesus monkeys that reliably self-administered PCP (0.0056 or 0.01 mg/kg per i.v. infusion). Infusion rates at the highest dose were typically lower than those for vehicle or saline, suggesting behavioral activity. Together, these results suggest that at behaviorally active doses gavestinel is not PCP-like and is likely to have low abuse liability.