The CaMKII‐dependent phosphorylation of GABA(B) receptors in the nucleus accumbens was involved in cocaine‐induced behavioral sensitization in rats

BACKGROUND: Previous studies have established that the regulation of prolonged, distal neuronal inhibition by the GABA(B) heteroreceptor (GABA(B)R) is determined by its stability, and hence residence time, on the plasma membrane. AIMS: Here, we show that GABA(B)R in the nucleus accumbens (NAc) of rats affects the development of cocaine‐induced behavioral sensitization by mediating its perinucleus internalization and membrane expression. MATERIALS & METHODS: By immunofluorescent labeling, flow cytometry analysis, Co‐immunoprecipitation and open field test, we measured the role of Ca(2+)/calmodulin‐dependent protein kinase II (CaMKII) to the control of GABA(B)R membrane anchoring and cocaine induced‐behavioral sensitization. RESULTS: Repeated cocaine treatment in rats (15 mg/kg) significantly decreases membrane levels of GABA(B1)R and GABA(B2)R in the NAc after day 3, 5 and 7. The membrane fluorescence and protein levels of GABA(B)R was also decreased in NAc GAD(67) (+) neurons post cocaine (1 μM) treatment after 5 min. Moreover, the majority of internalized GABA(B1)Rs exhibited perinuclear localization, a decrease in GABA(B1)R‐pHluroin signals was observed in cocaine‐treated NAc neurons. By contrast, membrane expression of phosphorylated CaMKII (pCaMKII) post cocaine treatment was significantly increased after day 1, 3, 5 and 7. Baclofen blocked the cocaine induced behavioral sensitization via inhibition of cocaine enhanced‐pCaMKII‐GABA(B1)R interaction. CONCLUSION: These findings reveal a new mechanism by which pCaMKII‐GABA(B)R signaling can promote psychostimulant‐induced behavioral sensitization.