RESUMEN
BACKGROUND: Previous studies have established that the regulation of prolonged, distal neuronal inhibition by the GABAB heteroreceptor (GABAB R) is determined by its stability, and hence residence time, on the plasma membrane. AIMS: Here, we show that GABAB 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 Ca2+ /calmodulin-dependent protein kinase II (CaMKII) to the control of GABAB R membrane anchoring and cocaine induced-behavioral sensitization. RESULTS: Repeated cocaine treatment in rats (15 mg/kg) significantly decreases membrane levels of GABAB1 R and GABAB2 R in the NAc after day 3, 5 and 7. The membrane fluorescence and protein levels of GABAB R was also decreased in NAc GAD67 + neurons post cocaine (1 µM) treatment after 5 min. Moreover, the majority of internalized GABAB1 Rs exhibited perinuclear localization, a decrease in GABAB1 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-GABAB1 R interaction. CONCLUSION: These findings reveal a new mechanism by which pCaMKII-GABAB R signaling can promote psychostimulant-induced behavioral sensitization.