Abstract
Using schedule-controlled behavior in rats, we have reported (Life Sci. 22, 195, 1978) complete tolerance development to the phencyclidine (PCP)-induced rate depressant effect after 7 daily treatments of 4 mg/kg. A method was developed for the measurement of [3H]-PCP and metabolites in the brain and blood of male Sprague-Dawley rats. The assay method involved sample extraction and thin-layer chromatographic separation with nonlabeled standards of PCP, 4-phenyl-4-piperidinocyclohexanol, and 1-(1-phenylcyclohexyl)-4-hydroxypiperidine to obtain Rf reference values for the identification of the compounds in the extracts. Animals received 6 daily treatments of 0.9% saline or 4 mg/kg PCP i.p. prior to administration of 4 mg/kg [3H]-PCP (96 μCi/kg i.p.) on day 7. The peak brain levels of [3H]-PCP were detected at 15 minutes after i.p. injection in both groups, and the concentrations of the parent compound and metabolites in the acute and subacute animals were not significantly different. These data argue against a dispositional mechanism of tolerance for this particular subacute dosing regimen. The time of maximum brain levels of PCP after the 4 mg/kg i.p. dose is in excellent correlation with the peak behavioral effects for both schedule-controlled behavior and the PCP-induced stereotyped behavioral syndrome.