Sigma2 (sigma2) receptors as a target for cocaine action in the rat striatum.
Studies from our laboratory have shown that agonists at sigma1 and sigma2 receptors inhibit N-methyl-D-aspartate (NMDA)-stimulated dopamine release from motor and limbic areas of rat brain. In the current study, we examined the effects of cocaine on N-methyl-D-aspartate (NMDA)-stimulated [3H]dopamine release in rat striatal slices. Cocaine inhibited N-methyl-D-aspartate-stimulated [3H]dopamine release in a concentration-dependent manner with a Ki of approximately 10 microM, under conditions in which the dopamine transporter (DAT) was blocked by 10 microM nomifensine. The inhibition seen by cocaine was reversed by the selective sigma2 antagonist 1'-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1-butyl]-spiro[isobenzofuran-1(3H), 4'piperidine] (Lu28-179). Inhibition of release by cocaine and (+)pentazocine, under conditions in which sigma1 receptors were blocked, was also reversed by the conventional PKC inhibitor 3-[1-[3-(dimethylamino)propyl-1H-indole-3-yl]-1-H-pyrpole-2-5'-dione. These results suggest that cocaine or other agonists, acting through the sigma2 receptor, require an intact conventional PKC (cPKC), most likely PKCalpha or PKCgamma in order to inhibit dopamine release.
Department of Pharmacology and Physiology, The George Washington University Medical Center, 2300 Eye Street NW, Washington, DC 20037, USA.
Samer J
SJ
Nuwayhid
Linda L
LL
Werling
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008698:Mesylates / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009627:Nomifensine / Q000494:pharmacology; D010423:Pentazocine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000502:physiology; D013141:Spiro Compounds / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014316:Tritium; D000097605:Sigma-1 Receptor; D000096926:Benzenesulfonamides
D001596:Benzylamines; D002118:Calcium; D003042:Cocaine; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D008698:Mesylates; D016202:N-Methylaspartate; D009627:Nomifensine; D010423:Pentazocine; D010880:Piperidines; D011493:Protein Kinase C; D011758:Pyrroles; D017480:Receptors, sigma; D013141:Spiro Compounds; D013449:Sulfonamides; D014316:Tritium; D000097605:Sigma-1 Receptor; C434605:5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate; C109644:Lu 28-179; C106107:sigma-2 receptor; C072105:KN 93; D000096926:Benzenesulfonamides; C078773:DuP 734; C070515:bisindolylmaleimide I