Evaluation of phencyclidine analogs on the basis of their discriminative stimulus properties in the rat
Shannon, H.E.
Journal of Pharmacology and Experimental Therapeutics 216(3): 543-551
1981
ISSN/ISBN: 0022-3565 PMID: 7205636 Document Number: 176022
Rats were trained in a 2-choice, discrete-trial avoidance procedure to discriminate between saline and 3.0 mg/kg of phencyclidine (PCP). Behavior was considered to be under stimulus control when the rats completed at least 90% of the trials in a 20-trial session on the PCP-appropriate choice lever after receiving PCP and when they completed at least 90% of the trials on the saline-appropriate choice lever after receiving saline. PCP analogs from several chemical families and the 2 monohydroxy metabolites of PCP were tested to determine their capacity to produce PCP-like discriminative stimuli as measured by responding on the PCP-appropriate choice lever and some of the structural requirements for producing PCP-like activity. Prototypes of other classes of psychoactive drugs were tested to determine the pharmacologic characteristics of the discriminative stimuli produced by PCP. PCP produced dose-related discriminative effects when tested over a > 10-fold dose range. PCP-like stimuli were produced by 13 analogs of PCP and 4-hydroxypiperidine metabolite but not by the 4-hydroxycyclohexane metabolite nor by 3 carbonitrile synthetic intermediates. The relative potencies for drugs which produced PCP-like stimuli ranged from N-ethyl-1-phenylcyclohexylamine (5.79 .times. PCP) to 1-[1-(2-thienyl)-cyclohexyl] morpholine (0.07 .times. PCP). Substitutions on the nitrogen atom were not required for producing PCP-like activity, whereas an electron-dense area in the region of the aromatic ring was essential. Of the 11 psychoactive drugs tested from other classes, only the psychotomimetic opioid derivative SKF-10,047 (2'-hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan) produced stimuli which were generalized to those produced by the training dose of PCP. These results indicate that PCP represents a unique class of drugs, but this class appears to have either physiologic actions or mechanisms of action in common with psychotomimetic opioid derivatives.