Fourphit, an acylating phencyclidine derivative, attenuates cocaine-induced hyperactivity in rats

Fourphit (4-isothiocyanato-1-[1-phenylcyclohexyl]piperidine), an acylating phencyclidine derivative that irreversibly inhibits stimulant binding 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. Administration of Fourphit (20 mg/kg, i.v.) significantly reduced the hyperactivity caused by challenge with either 15 or 40 mg/kg (-)cocaine x HCl (i.p.) 24 h later. It also increased the amount of thigmotaxis and decreased the rearing frequency of rats given the higher dose of cocaine. Only negligible 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 administration, however, was moderately depressed. Contrary to the results predicted from its activity in vitro, Fourphit did not inhibit the ex vivo binding of [3H]methylphenidate to stimulant receptors in the striatal tissue of treated rats. These results show that Fourphit can antagonize some behavioral actions of cocaine, but these effects are not likely due to covalent modification of the site on the dopamine transporter recognized by cocaine.