Phencyclidine-like abuse liability and psychosis-like neurocognitive effects of novel arylcyclohexylamine drugs of abuse in rodents

Abstract

Abuse of novel arylcyclohexylamines (ACX) poses risks for toxicities including adverse neurocognitive effects. In vivo effects of ring-substituted analogs of phencyclidine (PCP), eticyclidine (PCE), and ketamine are understudied. Adult male NIH Swiss mice were used to assess locomotor effects of PCP and its 3-OH, 3-MeO, 3-Cl and 4-MeO analogs; PCE and its 3-OH and 3-MeO analogs; and ketamine and its deschloro and 2F-deschloro analogs, in comparison to those of methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA), and two benzofuran analogs of MDMA. PCP-like interoceptive effects for all of these ACXs were determined using a food-reinforced drug discrimination procedure in adult male Sprague Dawley rats. A novel operant assay of rule-governed behavior incorporating aspects of attentional set-shifting was used to profile psychosis-like neurocognitive effects of PCP and 3-Cl-PCP in rats, in comparison to cocaine and morphine. PCP-like ACXs were more effective locomotor stimulants than the amphetamines, PCE-like ACXs were as effective as the amphetamines, and ketamine-like ACXs were less effective than the amphetamines. Addition of -Cl, -OH, or -OMe at the 3-position on the aromatic ring did not impact locomotor effectiveness, but addition of -OMe at the 4-position reduced locomotor effectiveness. Lethal effects were induced by drugs with -OH at the 3-position or -OMe at the 3- or 4-position. All novel ACXs substituted at least partially for PCP, and PCP and 3-Cl-PCP elicited dose-dependent psychosis-like neurocognitive deficits in the rule governed behavior task not observed with cocaine or morphine. Novel ACXs exhibit substantial abuse liability and toxicities not necessarily observed with their parent drugs. Significance Statement Novel arylcyclohexylamine analogs of PCP, PCE and ketamine are appearing on the illicit market, and abuse of these drugs poses risks for toxicities including adverse neurocognitive effects. These studies demonstrate that the novel ACXs exhibit PCP-like abuse liability in the drug discrimination assay, elicit varied locomotor stimulant and lethal effects in mice, and induce psychosis-like neurocognitive effects in rats.

Keywords: cognition; drug abuse; drug discrimination; structure-activity relationships.