Discriminative stimulus effects of N-substituted analogs of phencyclidine in rhesus monkeys

In daily sessions of a two-lever, discrete-trial, food-reinforced procedure, rhesus monkeys were trained to discriminate between subcutaneous injections of ketamine (1.0 or 1.8 mg/kg) and control injections. In tests of stimulus generalization, cumulative doses of drugs were administered in single sessions and either control- or ketamine-appropriate responding produced food. Ketamine (1.8 and 3.2 mg/kg) and phencyclidine (0.32 mg/kg) produced an average of more than 90% ketamine-appropriate responding. In contrast, d-amphetamine, atropine, chlorpromazine, codeine, diazepam and quipazine, tested at doses up to and including those that markedly reduced response rates, produced exclusively control-appropriate responding. Dose-related ketamine-appropriate responding was produced by each of ten 1-phenylcyclohexylamines, the potencies of which varied with the length, electronegativity, and number of N-alkyl chains present. The most potent analog of phencyclidine, N-ethyl-1-phenylcyclohexylamine, was approximately equipotent with phencyclidine. These data are consistent with previous reports that the discriminative stimulus effects produced by phencyclidine are representative of a unique class of drugs, and that alkyl substitutions in the region of the piperidine ring alter the potency, but not the characteristic pharmacological activity, of the resulting analogs. The potencies of some of these analogs compared to phencyclidine in rhesus monkeys, however, differed from their relative potencies in rodents. Thus, there appear to be species differences in the role of the nitrogen pharmacophore of these compounds in producing phencyclidine-like behavioral effects.