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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 257; no. 1; p. 141
• Main Authors: Itzhak, Y, Stein, I, Zhang, S H, Kassim, C O, Cristante, D
• Format: Journal Article
• Language: English
• Published: United States 01-04-1991
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - metabolism; Animals; Binding Sites; Brain - metabolism; Guanidines - metabolism; In Vitro Techniques; Ligands; Male; Mice; Mice, Inbred C57BL; Monoamine Oxidase Inhibitors - metabolism; Monoamine Oxidase Inhibitors - pharmacology; Phenazocine - analogs & derivatives; Phenazocine - metabolism; Piperidines - metabolism; Receptors, Opioid - analysis; Receptors, Opioid - metabolism; Receptors, sigma
• ISSN: 0022-3565

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.