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A comparison between classes of drugs having phencyclidine-like behavioral properties on dopamine efflux in vitro and dopamine metabolism in vivo

LD Snell, ZL Mueller, RL Gannon, PB Silverman and KM Johnson

Phencyclidine [(l-phenylcyclohexyl) piperidine] (PCP) is known to increase the basal efflux of striatal dopamine (DA) in vitro and to enhance haloperidol (HAL)-induced striatal DA metabolism in vivo. This study compared these activities of PCP to several representatives of the arylcyloalkylamine, benzomorphan and substituted dioxolane classes whose behavioral similarities to PCP have been well studied. The affinity of these drugs for the PCP/sigma opiate receptor also was estimated by determining the concentration of these drugs required to inhibit the specific binding of 10 nM [3H]PCP to rat cortical membranes by 50%. Of the arylcycloalkylamines tested on the basal efflux of [3H]DA, we found the rank-order effectiveness to be as follows: PCP greater than 1-[l-(napthyl)cyclohexyl]piperidine HCl (m-amino-PCP) greater than ketamine greater than or equal to 1-[l-(m- nitrophenyl)cyclohexyl]piperidine HCl (m-nitro-PCP) greater than N- ethyl-l-phencyclohexylamine (PCE). However, in vivo we found that PCP, m-amino-PCP and PCE significantly elevated HAL-induced DA metabolism, whereas ketamine and m-nitro-PCP were without effect. Although each of the benzomorphans tested [N-allylnormetazocine (NANM) and ethylketocyclazocine (EKC)] slightly enhanced the basal efflux of [3H]DA from striatal slices, concentrations of 10 to 30 microM were required to elicit the same magnitude of [3H]DA release caused by 3 microM PCP. Quantitatively similar responses were produced by the substituted dioxolanes tested (etoxadrol, dexoxadrol and levoxadrol). Neither (+)-NANM, (-)-NANM, (+/-)-NANM, etoxadrol nor dexoxadrol had any effect on HAL-induced DA metabolism. On the other hand, both levoxadrol and EKC significantly decreased the ratio of HVA/DA after HAL administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 231, Issue 2, pp. 261-269, 11/01/1984
Copyright © 1984 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1984 by the American Society for Pharmacology and Experimental Therapeutics.