Title

Regulation of [3H]norepinephrine release from guinea pig hippocampus by σ2 receptors

Document Type

Journal Article

Publication Date

5-20-1997

Journal

European Journal of Pharmacology

Volume

326

Issue

2-3

DOI

10.1016/S0014-2999(97)85407-6

Keywords

BIMU-8 (+)-Pentazocine; Hippocampus; Norepinephrine; σ Receptor 2

Abstract

The binding profile of the σ2 receptor ligand endo-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)-2,3-dihydro-(1-methyl)ethyl-2 -oxo-1H-benzimidazole-1- carboxamidehydrochloride (BIMU-8) had previously been determined, but its agonist/antagonist status at σ2 receptors had not been identified. We therefore investigated the effects of BIMU-8 for its ability to regulate the stimulated release of [3H]norepinephrine from slices of guinea pig hippocampus. BIMU-8 alone, at a concentration chosen to occupy 50% of σ2 receptors, had no significant effect on N-methyl-D-aspartate (NMDA)-stimulated release of [3H]norepinephrine. We have shown previously that the a receptor agonist(+)-pentazocine inhibits NMDA-stimulated release in a concentration-dependent manner, producing a biphasic inhibition curve. Similarly, the σ receptor agonist 1S,2R-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl (BD737) produced a broad inhibition curve. The inhibition by low concentrations of(+)-pentazocine or BD737 that selectively activated σ1 receptors was reversed by the σ1-selective receptor antagonist (1-(cyclopropylmethyl)-4-2'-oxoethyl)piperidine HBr (DuP 734). In the current study, when the σ1 component of inhibition by (+)-pentazocine was blocked by DuP 734, the remaining component of inhibition mediated by σ2 receptors was reversed by BIMU-8. Our results suggest that (1) BIMU-8 is an antagonist at σ2 receptors and that (2) σ2 receptors contribute to regulation of norepinephrine release in guinea pig hippocampus.

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