RT Journal Article
SR Electronic
T1 Steroids Modulate <em>N</em>-Methyl-D-aspartate-Stimulated
 [<sup>3</sup>H]Dopamine Release from Rat Striatum via σ Receptors
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 934
OP 940
DO 10.1124/jpet.103.052324
VO 306
IS 3
A1 Samer J. Nuwayhid
A1 Linda L. Werling
YR 2003
UL http://jpet.aspetjournals.org/content/306/3/934.abstract
AB 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-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 PKCβ-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 σ receptors. The American Society for Pharmacology and Experimental Therapeutics