Sigma2 (σ2) receptors as a target for cocaine action in the rat striatum

Studies from our laboratory have shown that agonists at sigma, and sigma(2) 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 [H-3]dopamine release in rat striatal slices. Cocaine inhibited N-methyl-D-aspartate-stimulated [H-3]dopamine release in a concentrationdependent manner with a K-i of approximately 10 mu M, under conditions in which the dopamine transporter (DAT) was blocked by 10 mu M nornifensine. The inhibition seen by cocaine was reversed by the selective sigma(2) 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 sigma I 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 sigma(2), receptor, require an intact conventional PKC (cPKC), most likely PKC alpha or PKC gamma in order to inhibit dopamine release. (c) 2006 Elsevier B.V All rights reserved.