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

Yossef Itzhak, I. Stein, S. H. Zhang, C. O. Kassim, D. Cristante

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Abstract

Our preliminary studies indicated that certain monoamine oxidase (MAO) inhibitors display high affinity for the σ-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/σ-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/σ-sites is competitive and reversible unlike the interaction of clorgyline with MAO-A. The σ-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. These findings suggest that clorgyline-sensitive/σ-binding sites may coexist with MAO in the mitochondrial fraction of mouse brain. High density of DTG binding sites is present in the microsomal fraction of the mouse brain, which also constitutes high density of (+)-3-PPP/(+)SKF 10047 binding sites.

Original languageEnglish
Pages (from-to)141-148
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume257
Issue number1
StatePublished - Jan 1 1991

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Monoamine Oxidase Inhibitors
Inbred C57BL Mouse
Binding Sites
Ligands
Clorgyline
Membranes
Monoamine Oxidase
Brain
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Selegiline
preclamol
Guanidine
Haloperidol
SK&F 10047

ASJC Scopus subject areas

  • Pharmacology

Cite this

Binding of σ-ligands to C57BL/6 mouse brain membranes : Effects of monoamine oxidase inhibitors and subcellular distribution studies suggest the existence of σ-receptor subtypes. / Itzhak, Yossef; Stein, I.; Zhang, S. H.; Kassim, C. O.; Cristante, D.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 257, No. 1, 01.01.1991, p. 141-148.

Research output: Contribution to journalArticle

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