Reversal of cocaine sensitization-induced behavioral sensitization normalizes GAD67 and GABAA receptor alpha2 subunit expression, and PKC zeta activity.

We have recently shown in rats that cocaine-induced behavioral sensitization can be reversed by a 5-day treatment with ondansetron given 3.5 h after daily pergolide injections. In this study we further investigated the molecular/neurochemical alterations underlying cocaine sensitization and pergolide/ondansetron-mediated reversal. Results revealed that glutamic acid decarboxylase (GAD(65)/GAD(67)) is higher abundant in the nucleus accumbens (NAc) than that in the caudate and medial prefrontal cortex (mPFC), while GABA(A) receptor alpha2 subunit level in the NAc shell is less abundant than that in the NAc core, mPFC and caudate. Cocaine sensitization led to (1) a decrease in GAD(67) expression, an increase in total protein kinase C (PKC) zeta subtype and phosphorylated PKC zeta/lambda levels in the NAc core; (2) a decrease in GAD(67) and GABA(A) receptor alpha2 subunit expression, and an increase in phosphorylated PKC zeta/lambda levels in the NAc shell; (3) an increase in GAD(67) expression in the caudate. Importantly, pergolide/ondansetron treatment reversed these alterations. These results suggest that reversal of cocaine-induced behavioral sensitization is associated with reversal of region-specific changes in GABA function and PKC activity in the striatum.