Metaphit, which acylates phencyclidine (PCP) receptors in vitro, was shown to acylate PCP receptors and antagonize the behavioral and electrophysiological effects of PCP in vivo. Metaphit (2 μmol/rat) administered i.c.v. produced PCP-like stereotyped behavior and ataxia in 10 to 20% of rats. At a lower dose, Metaphit (1 μmol/rat) antagonized the ability of PCP to induce stereotyped behavior and ataxia for 3 and 4 days, respectively. The Metaphit-induced antagonism of PCP induction of stereotyped behavior and ataxia was dose-dependent and specific as Metaphit did not antagonize induction of stereotyped behavior by amphetamine. Further evidence for a specific PCP receptor mechanism was the finding that PCP pretreatment blocked the effects of subsequent Metaphit administration. Metaphit also antagonized PCP-induction of stereotyped behavior, but not ataxia, after i.v. administration. Doses of Metaphit that produced long-term antagonism of the behavioral effects of PCP also produced a significant decrease in the maximum binding, but not K(d), of the binding of the PCP analog, [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine, in Metaphit-pretreated rats. The binding of [3H]etorphine and [3H]spiroperidol was not altered significantly by pretreating rats with Metaphit. (-)-Cyclazocine and (+)-SKF 10,047 induced stereotyped behavior and ataxia that was not antagonized by Metaphit-pretreatment. In electrophysiological experiments, Metaphit, like PCP, initially depressed the firing of caudate neurons as does PCP, but then irreversibly inhibited PCP-induced depression of caudate neurons. These results suggest that metaphit antagonized the effects of PCP by selectively acylating PCP receptors and that (-)-cyclazocine- and (+)-SKF 10,047-induced behavioral effects are not mediated primarily by PCP receptors.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1986|
ASJC Scopus subject areas
- Molecular Medicine