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NEUROPHARMACOLOGY

Steroids Modulate N-Methyl-D-aspartate-Stimulated [³H]Dopamine Release from Rat Striatum via Receptors

Department of Pharmacology, George Washington University Medical Center, Washington, DC

Steroids have been proposed as endogenous ligands at 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 K_i values for these steroids obtained in binding studies, and was fully reversed by both the ₁ antagonist 1-(cyclopropylmethyl)-4-2'-4''flurophenyl)-2'oxoethyl)piperidine HBr (DuP734) and the ₂ antagonist 1'-[4-[1-(4-fluorophenyl)-1-H-indol-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 PKC-selective inhibitor 5,21:12,17-dimetheno-18H-dibenzo[i,o]pyrrolo[3,4 - 1][1,8]diacyclohexadecine-18,20(19H)-dione,8-[(dimethylamino)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 receptors.

Address correspondence to: Dr. Linda L. Werling, Department of Pharmacology, The George Washington University, 2300 Eye St., NW, Washington, DC 20037. E-mail: phmllw{at}gwumc.edu

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