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-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.
Footnotes
-
This work was supported by a grant from National Institute on Drug Abuse (DA06667) and a Faculty Enhancement Research Award from George Washington University Medical Center (to L.L.W.).
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
DOI: 10.1124/jpet.103.052324.
-
ABBREVIATIONS: NMDA, N-methyl-d-aspartate; DHEA S, dehydroepiandrosterone sulfate; PREG S, pregnenolone sulfate; DHEA, dehydroepiandrosterone; PKC, protein kinase C; PLC, phospholipase C; MKB, modified Krebs-HEPES buffer; S1, first stimulus; ISI, inter stimulus interval; S2, second stimulus; LY379196, 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); BD1063, 1[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine; DuP734, 1-(cyclopropylmethyl)-4-2′-4″flurophenyl)-2′oxoethyl)piperidine HBr; Lu28-179, 1′-[4-[1-(4-fluorophenyl)-1-H-indol-3-yl]-1-butyl]spiro[iso-benzofuran-1(3H),4′piperidine]; GF109203x, 3[1-[3-(dimethylamino)propyl]-1H-indol-3-yl)-1-H-pyrprole-2,5-dione; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; SKF10,047, n-allylnormetazocine; BD737, 1S,2R-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)-cyclyohexylamine; U73122, 1(6-((17-b-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione.
- Received March 31, 2003.
- Accepted May 13, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|