Steroids modulate N-methyl-D-aspartate-stimulated [3H]dopamine release from rat striatum via σ receptors

Document Type

Journal Article

Publication Date

9-1-2003

Journal

Journal of Pharmacology and Experimental Therapeutics

Volume

306

Issue

3

DOI

10.1124/jpet.103.052324

Abstract

Steroids have been proposed as endogenous ligands at σ receptors. In the current study, we examined the ability of steroids to regulate N-methyl-D-aspartate (NMDA)-stimulated [3H]dopamine release from slices of rat striatal tissue. We found that both progesterone and pregnenolone inhibit [3H]dopamine release in a concentration-dependent manner similarly to prototypical agonists, such as (+)-pentazocine. The inhibition seen by both progesterone and pregnenolone exhibits IC50 values consistent with reported Ki values for these steroids obtained in binding studies, and was fully reversed by both the σ1 antagonist 1-(cyclopropylmethyl)-4-2′-4′′flurophenyl)-2′oxoethyl) piperidine HBr (DuP734) and the σ2 antagonist 1′-[4-[1-(4-fluorophenyl)-1-Hindol-3-yl]-1-butyl] spiro[iso-benzofuran-1(3H), 4′piperidine] (Lu28-179). Lastly, to determine whether a protein kinase C (PKC) signaling system might be involved in the inhibition of NMDA-stimulated [3H]dopamine release, we tested the PKCβ-selective inhibitor 5,21:12,17-dimetheno-18H-dibenzo[i,o]pyrrolo[3,4-1][1,8]diacyclohexadecine-18, 20(19H)-dione,8-[(dimethylamin-o)methyl]-6,7,8,9,10, 11-hexahydro-monomethanesulfonate (9Cl) (LY379196) against both progesterone and pregnenolone. We found that LY379196 at 30 nM reversed the inhibition of release by both progesterone and pregnenolone. These findings support steroids as candidates for endogenous ligands at σ receptors.

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