Inhibition of carbachol-induced inositol phosphate accumulation by phencyclidine, phencyclidine-like ligands and sigma agonists involves blockade of the muscarinic cholinergic receptor: a novel dioxadrol-preferring interaction.
The effect of phencyclidine (PCP) on carbachol-induced phosphoinositol hydrolysis was examined in rat brain slices taken from cortex, caudate-putamen and hippocampus. In all three regions studied, PCP significantly inhibited carbachol-induced [3H]inositol phosphate accumulation working as low as 10(-6) M in the cerebral cortex. Because PCP has been shown to act at two sites, a PCP-site and a sigma site, various PCP-like agonists [levoxadrol (Lev), dexoxadrol (Dex) and MK-801 [(+)-5-methyl-10,11-dihydro- 5H-dibenzo(a,b)cyclo-hepaten-5, 10-imine maleate]] as well as sigma agonists [(+)-SKF10047 and 1,3-di(2-toly)guanidine (DTG) were examined for their effects on carbachol-induced phosphoinositol hydrolysis. All but MK-801 significantly inhibited the carbachol action; however, their order of potencies, Lev greater than or equal to Dex much greater than PCP greater than or equal to DTG greater than or equal to (+)-SKF10047 differed from those of other known PCP interactions at PCP and sigma sites. Inasmuch as it is known that PCP competes for binding at muscarinic sites, we examined the effects of PCP, Lev, Dex, DTG and MK-801 on the binding of L-[3H]-3-quinuclidinyl benzilate to its muscarinic site. All blocked L-[3H]-3-quinuclidinyl benzilate binding and exhibited a rank order of potency almost identical to that obtained in the inositol studies with Lev greater than Dex much much greater than DTG much greater than PCP MK-801. In addition, the IC50 values obtained from both studies were very similar. It is concluded that PCP, PCP-like compounds and sigma agonists block carbachol-induced inositol-phosphate accumulation by blockade of muscarinic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, St. Louis University Medical School, Missouri.
J S
JS
Brog
M C
MC
Beinfeld
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002217:Carbachol / Q000037:antagonists & inhibitors*; D046508:Culture Techniques; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004148:Dioxolanes; D016291:Dizocilpine Maleate; D007295:Inositol Phosphates / Q000378:metabolism*; D008297:Male; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology*; D010880:Piperidines; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D012808:Sigma Factor / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D003986:Dibenzocycloheptenes; D004148:Dioxolanes; D007295:Inositol Phosphates; D010880:Piperidines; D011976:Receptors, Muscarinic; D012808:Sigma Factor; D014157:Transcription Factors; C005840:dioxadrol; D016291:Dizocilpine Maleate; C012134:SK&F 10047; C579649:levoxadrol; D002217:Carbachol; D010620:Phenazocine; D010622:Phencyclidine; C579650:dexoxadrol