title: Metaphit, an acylating ligand for phencyclidine receptors: characterization of in vivo actions in the rat.
abstract: 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 mumol/rat) administered i.c.v. produced PCP-like stereotyped behavior and ataxia in 10 to 20% of rats. At a lower dose, Metaphit (1 mumol/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 Kd, of the binding of the PCP analog, [3H]-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.
mesh_terms: D000215:Acylation; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D002421:Caudate Nucleus / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008024:Ligands; D008297:Male; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D011957:Receptors, Opioid / Q000187:drug effects; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D008024:Ligands; D011954:Receptors, Dopamine; D017981:Receptors, Neurotransmitter; D011957:Receptors, Opioid; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; C012058:tenocyclidine; C044705:metaphit; D000661:Amphetamine; D010622:Phencyclidine