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

• Published in: CNS neuroscience & therapeutics 2023-05, Vol.29 (5), p.1345-1356
• Main Authors: Lu, Ming F., Fu, Qiang, Qiu, Tian Y., Yang, Jian H., Peng, Qing H., Hu, Zhen Z.
• Format: Article
• Language: English
• Subjects: Addictions; Antibodies; Baclofen; behavioral sensitization; Brain; Ca2+/calmodulin-dependent protein kinase II; Calcium-binding protein; Calmodulin; CaMKII; Cocaine; Dopamine; Experiments; Field study; Flow cytometry; GABABR; Immunoprecipitation; Internalization; Kinases; Laboratory animals; Localization; Membrane proteins; Neurons; Neurosciences; Nucleus accumbens; Open-field behavior; Original; Phosphorylation; Proteins; γ-Aminobutyric acid B receptors
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.14107

Background Previous studies have established that the regulation of prolonged, distal neuronal inhibition by the GABAB heteroreceptor (GABABR) is determined by its stability, and hence residence time, on the plasma membrane. Aims Here, we show that GABABR 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 GABABR membrane anchoring and cocaine induced‐behavioral sensitization. Results Repeated cocaine treatment in rats (15 mg/kg) significantly decreases membrane levels of GABAB1R and GABAB2R in the NAc after day 3, 5 and 7. The membrane fluorescence and protein levels of GABABR was also decreased in NAc GAD67+ neurons post cocaine (1 μM) treatment after 5 min. Moreover, the majority of internalized GABAB1Rs exhibited perinuclear localization, a decrease in GABAB1R‐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‐GABAB1R interaction. Conclusion These findings reveal a new mechanism by which pCaMKII‐GABABR signaling can promote psychostimulant‐induced behavioral sensitization. This work was shown that GABAB receptors (GABABR) in GABAergic neurons of the nucleus accumbens (NAc) potentially regulates cocaine‐induced locomotor sensitization. Furthermore, baclofen (GABABR agonist) can block cocaine‐induced locomotor sensitization via the recovery of surface expression of GABABR from cocaine‐induced inhibition. Baclofen enhanced‐GABABR membrane internalization and anchoring could be attributed to the suppression of cocaine‐induced enhance of interaction of pCaMKII–GABAB1R.