Metformin Prevents Cocaine Sensitization: Involvement of Adenosine Monophosphate-Activated Protein Kinase Trafficking between Subcellular Compartments in the Corticostriatal Reward Circuit.
Metformin Prevents Cocaine Sensitization: Involvement of Adenosine Monophosphate-Activated Protein Kinase Trafficking between Subcellular Compartments in the Corticostriatal Reward Circuit.
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DOI：
10.3390/ijms242316859
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发表时间：
2023-11-28
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
反复接触可卡因会产生一种增强的运动反应（敏化作用），同时大脑中会出现生物学适应性变化。先前的研究表明，腺苷酸活化蛋白激酶（AMPK）对反复接触可卡因具有区域特异性反应。AMPK在机体和细胞水平维持细胞能量稳态。在此，我们的目的是量化急性或敏化性可卡因注射后内侧前额叶皮质、伏隔核和背侧纹状体的细胞质和突触小体中磷酸化（活性）AMPK和总AMPK的变化。发现AMPK和磷酸化AMPK（pAMPK）在脑区和细胞区室存在选择性变化，且在急性戒断与持续可卡因治疗方面存在一些差异。我们的另一个目标是确定间接AMPK激活剂二甲双胍预处理的行为和分子效应。二甲双胍增强了急性可卡因的运动激活作用，但阻断了敏化作用的发展。性别差异在很大程度上掩盖了任何蛋白质水平的治疗组效应，尽管在接受反复可卡因的大鼠中，伏隔核壳细胞质中的pAMPK令人惊讶地被二甲双胍降低。这些研究的基本原理是增进我们对亚细胞区室中AMPK激活动力学的理解，并为将二甲双胍重新用于治疗可卡因使用障碍提供额外支持。
Repeated cocaine exposure produces an enhanced locomotor response (sensitization) paralleled by biological adaptations in the brain. Previous studies demonstrated region-specific responsivity of adenosine monophosphate-activated protein kinase (AMPK) to repeated cocaine exposure. AMPK maintains cellular energy homeostasis at the organismal and cellular levels. Here, our objective was to quantify changes in phosphorylated (active) and total AMPK in the cytosol and synaptosome of the medial prefrontal cortex, nucleus accumbens, and dorsal striatum following acute or sensitizing cocaine injections. Brain region and cellular compartment selective changes in AMPK and pAMPK were found with some differences associated with acute withdrawal versus ongoing cocaine treatment. Our additional goal was to determine the behavioral and molecular effects of pretreatment with the indirect AMPK activator metformin. Metformin potentiated the locomotor activating effects of acute cocaine but blocked the development of sensitization. Sex differences largely obscured any protein-level treatment group effects, although pAMPK in the NAc shell cytosol was surprisingly reduced by metformin in rats receiving repeated cocaine. The rationale for these studies was to inform our understanding of AMPK activation dynamics in subcellular compartments and provide additional support for repurposing metformin for treating cocaine use disorder.
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