The CaMKII-dependent phosphorylation of GABAB receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats

Abstract

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 Ca²⁺ /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 GAD₆₇ ⁺ 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.

Keywords: CaMKII; GABABR; behavioral sensitization; cocaine; nucleus accumbens; phosphorylation.