Reversal of cocaine sensitization-induced behavioral sensitization normalizes GAD 67 and GABA A receptor α2 subunit expression, and PKC ζ activity

Abstract

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 α2 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) ζ subtype and phosphorylated PKC ζ/λ levels in the NAc core; (2) a decrease in GAD 67 and GABA A receptor α2 subunit expression, and an increase in phosphorylated PKC ζ/λ 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.