FOURPHIT, AN ACYLATING PHENCYCLIDINE DERIVATIVE, ATTENUATES COCAINE-INDUCED HYPERACTIVITY IN RATS

Fourphit -isothiocyanato-1-[1-phenylcyclohexyl]piperidine), an acylati ng phencyclidine derivative that irreversibly inhibits stimulant bindi ng to the dopamine transporter in vitro (Schweri et al., J. Pharmacol. Exp. Ther. 261:936-942, 1992), was tested in rats for its ability to block the increased locomotor activity caused by cocaine. Administrati on of Fourphit (20 mg/kg, IV) significantly reduced the hyperactivity caused by challenge with either 15 or 40 mg/kg (-)cocaine.HCl (LP) 24 h later. It also increased the amount of thigmotaxis and decreased the rearing frequency of rats given the higher dose of cocaine. Only negl igible effects on behavior were found upon acute administration of the compound by itself, or in response to a saline challenge 24 h later. Activity during the dark cycle immediately following Fourphit administ ration, however, was moderately depressed. Contrary to the results pre dicted from its activity in vitro, Fourphit did not inhibit the ex viv o binding of [H-3]methylphenidate to stimulant receptors in the striat al tissue of treated rats. These results show that Fourphit can antago nize some behavioral actions of cocaine, but these effects are not lik ely due to covalent modification of the site on the dopamine transport er recognized by cocaine. (C) 1998 Elsevier Science Inc.