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

Steroids have been proposed as endogenous ligands at sigma receptors. In the current study, we examined the ability of steroids to regulate N-methyl-D-aspartate (NMDA)-stimulated [H-3]dopamine release from slices of rat striatal tissue. We found that both progesterone and pregnenolone inhibit [H-3]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 sigma(1) antagonist 1-(cyclopropylmethyl)-4-2'-4flurophenyl)-2' oxoethyl)piperidine HBr (DuP734) and the sigma(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 [H-3]dopamine release, we tested the PKCbeta-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 sigma receptors.