The CaMKII-dependent phosphorylation of GABA(B) receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats.
The CaMKII-dependent phosphorylation of GABA(B) receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats.
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DOI：
10.1111/cns.14107
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发表时间：
2023-05
影响因子：
5.5
通讯作者：
中科院分区：
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先前的研究已经确定，GABAB异源受体（GABABR）对长时间远端神经元抑制的调节是由其在质膜上的稳定性和停留时间决定的。在这里，我们表明，GABABR在大鼠延髓核（NAc）影响可卡因诱导的行为敏化的发展，通过介导其核周内化和膜表达。通过免疫荧光标记、流式细胞仪分析、免疫共沉淀和旷场实验，我们检测了Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）在GABABR膜锚定和可卡因诱导的行为敏化中的作用。重复可卡因治疗大鼠（15毫克/公斤）显着降低膜水平的GABAB 1 R和GABAB 2 R的NAc后3，5和7天。可卡因（1 μM）处理5 min后，NAc GAD 67+神经元中GABABR的膜荧光和蛋白水平也降低。此外，大多数内化的GABAB 1 R表现出核周定位，在可卡因处理的NAc神经元中观察到GABAB 1 R-pHluroin信号减少。相比之下，可卡因处理后磷酸化CaMKII（pCaMKII）的膜表达在第1、3、5和7天后显著增加。巴氯芬通过抑制可卡因增强的-pCaMKII-GABAB 1 R相互作用阻断可卡因诱导的行为敏化。这些发现揭示了一种新的机制，pCaMKII‐GABABR信号可以促进精神兴奋剂诱导的行为敏化。这项工作表明，中脑核（NAc）的GABA能神经元中的GABAB受体（GABABR）可能调节可卡因诱导的运动敏化。此外，巴氯芬（GABABR激动剂）可通过从可卡因诱导的抑制中恢复GABABR的表面表达来阻断可卡因诱导的运动敏化。巴氯芬增强GABABR膜内化和锚定可能归因于可卡因诱导的pCaMKII-GABAB 1 R相互作用增强的抑制。
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. 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. 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. 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. 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.
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