title: Regulation of [3H]norepinephrine release from guinea pig hippocampus by sigma2 receptors.
abstract: The binding profile of the sigma2 receptor ligand endo-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)-2,3-dihydro-(1-methyl)eth yl-2-oxo-1H-benzimidazole-1-carboxamidehydrochloride (BIMU-8) had previously been determined, but its agonist/antagonist status at sigma2 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 sigma2 receptors, had no significant effect on N-methyl-D-aspartate (NMDA)-stimulated release of [3H]norepinephrine. We have shown previously that the sigma receptor agonist (+)-pentazocine inhibits NMDA-stimulated release in a concentration-dependent manner, producing a biphasic inhibition curve. Similarly, the sigma receptor agonist 1S,2R-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl )cyclohexylamine (BD737) produced a broad inhibition curve. The inhibition by low concentrations of (+)-pentazocine or BD737 that selectively activated sigma1 receptors was reversed by the sigma1-selective receptor antagonist (1-(cyclopropylmethyl)-4-2'-oxoethyl)piperidine HBr (DuP 734). In the current study, when the sigma1 component of inhibition by (+)-pentazocine was blocked by DuP 734, the remaining component of inhibition mediated by sigma2 receptors was reversed by BIMU-8. Our results suggest that (1) BIMU-8 is an antagonist at sigma2 receptors and that (2) sigma2 receptors contribute to regulation of norepinephrine release in guinea pig hippocampus.
authors.affiliation: Department of Pharmacology, The George Washington University Medical Center, Washington, DC 20037, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Weatherspoon
authors.forename: G M
authors.initials: GM
authors.lastname: Gonzalez-Alvear
authors.forename: L L
authors.initials: LL
authors.lastname: Werling
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006624:Hippocampus / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010423:Pentazocine / Q000037:antagonists & inhibitors; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000502:physiology*; D014316:Tritium
chemical_list: D001562:Benzimidazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017480:Receptors, sigma; D014316:Tritium; C070189:(endo-N-8-methyl-8-azabicyclo-(3.2.1)oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide; D010423:Pentazocine; D009638:Norepinephrine