Sigma(2) (sigma(2)) receptors as a target
for cocaine action in the rat striatum

Nuwayhid SJ, Werling LL.
Department of Pharmacology and Physiology,
The George Washington University Medical Center,
2300 Eye Street NW, Washington,
D.C. 20037, United States.
Eur J Pharmacol. 2006 Feb 7;


Studies from our laboratory have shown that agonists at sigma(1) 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 [(3)H]dopamine release in rat striatal slices. Cocaine inhibited N-methyl-d-aspartate-stimulated [(3)H]dopamine release in a concentration-dependent manner with a K(i) of approximately 10 muM, under conditions in which the dopamine transporter (DAT) was blocked by 10 muM nomifensine. 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(1) 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 PKCalpha or PKCgamma in order to inhibit dopamine release.

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