Protection with phencyclidine against inactivation of 5-HT₂ receptors by sulfhydryl-modifying reagents

We investigated whether phencyclidine (PCP)-induced head-twitch was antagonized in rats by ritanserin, a selective serotonin₂ (5-HT₂) receptor antagonist, to confirm the involvement of 5-HT neurons in PCP action and to discover whether PCP could protect the binding sites of [³H]PCP and [^3H]ketanserin from the inhibitory effect of protein-modifying reagents which affect sulfhydryl groups. PCP (7.5,10 and 12.5 mg/kg, i.p.)-induced head-twitch was completely antagonized by ritanserin (1 mg/kg, s.c.). Scatchard plots of specific [³H]PCP and [³H]ketanserin binding showed that sulfhydryl-modifying reagent, N-ethylmaleimide (NEM, 100 μM) caused a significant decrease in B_max without changing K_d. PCP (10 μM) and ritanserin (1 μM) protected [³H]PCP and [³H]ketanserin binding sites from the decrease in the number induced by NEM (100 μM). 5-HT protected [³H]5-HT binding sites from inactivation by NEM, but PCP and ritanserin did not show any effect. On the basis of the present findings, it is concluded that PCP can interact with 5-HT₂ receptors directly or allosterically, and 5-HT₂ receptors may locate at PCP binding sites in membranes.