Sigma2 (σ2) 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 μM, under conditions in which the dopamine transporter (DAT) was blocked by 10 μM nomifensine. The inhibition seen by cocaine was reversed by the selective σ2 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 σ2 receptor, require an intact conventional PKC (cPKC), most likely PKCα or PKCγ in order to inhibit dopamine release.