Binding of sigma-ligands to C57BL/6 mouse brain membranes: effects of monoamine oxidase inhibitors and subcellular distribution studies suggest the existence of sigma-receptor subtypes

Y Itzhak, I Stein, SH Zhang, CO Kassim and D Cristante

Department of Biochemistry and Molecular Biology, REPSCEND Laboratories, University of Miami School of Medicine, Florida 33101.

Our preliminary studies indicated that certain monoamine oxidase (MAO) inhibitors display high affinity for the sigma-binding sites labeled with (+)[3H]-3-(3-hydroxyphenyl)-N-1-(propyl)piperidine [(+)[3H]-3-PPP] in C57BL/6 mouse brain (Itzhak, Y., and Kassim, C. D.: Eur. J. Pharmacol. 176: 107-108, 1990). In the present study, the drug specificity and the subcellular distribution of (+)[3H]-3-PPP, (+)[3H]- N-allylnormetazocine [(+)[3H]SKF 10047] and [3H]1,3-di-o-tolyl- guanidine ([3H]DTG) binding sites in C57BL/6 mouse brain were investigated, and the properties of clorgyline interaction with the (+)- 3-PPP/sigma-binding site(s) were examined. (+)[3H]-3-PPP binding, but not [3H]DTG binding, is inhibited by low concentrations (nM) of the dextrorotatory (+)-isomers of SKF 10047, 3-PPP and deprenyl and the type A MAO inhibitor, clorgyline. The haloperidol-sensitive/(+)[3H]SKF 10047 binding sites display virtually identical sensitivity towards the MAO inhibitors as (+)-3-PPP binding sites. These observations suggest a distinction between [3H]DTG and (+)[3H]-3-PPP/(+)[3H]SKF 10047 binding sites in the mouse brain. Clorgyline interaction with (+)-3-PPP/sigma- sites is competitive and reversible unlike the interaction of clorgyline with MAO-A. The sigma-ligands tested do not inhibit MAO activity and bind to sites that are apparently distinct from the MAO binding sites labeled with [3H]-N-methyl-4-phenyl-1,2,3,6- tetrahydropyridine. However, the mitochondrial fraction of the mouse brain that expresses MAO activity and high density of [3H]-N-methyl-4- phenyl-1,2,3,6-tetrahydropyridine binding sites also comprises high density of (+)-3-PPP/(+)SKF 10047 binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 257, Issue 1, pp. 141-148, 04/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

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