PDF(Pubmed)
Abstract：
Repeated exposure to psychostimulants such as methamphetamine (METH) induces neuronal adaptations in the mesocorticolimbic dopamine system, including the ventral tegmental area (VTA). These changes lead to persistently enhanced neuronal activity causing increased dopamine release and addictive phenotypes. A factor contributing to increased dopaminergic activity in this system appears to be reduced GABAB receptor-mediated neuronal inhibition in the VTA. Dephosphorylation of serine 783 (Ser783) of the GABAB2 subunit by protein phosphatase 2A (PP2A) appears to trigger the downregulation GABAB receptors in psychostimulant-addicted rodents. Therefore, preventing the interaction of GABAB receptors with PP2A using an interfering peptide is a promising strategy to restore GABAB receptor-mediated neuronal inhibition. We have previously developed an interfering peptide (PP2A-Pep) that inhibits the GABAB receptors/PP2A interaction and thereby restores receptor expression under pathological conditions. Here, we tested the hypothesis that restoration of GABAB receptor expression in the VTA of METH addicted mice reduce addictive phenotypes. We found that the expression of GABAB receptors was significantly reduced in the VTA and nucleus accumbens but not in the hippocampus and somatosensory cortex of METH-addicted mice. Infusion of PP2A-Pep into the VTA of METH-addicted mice restored GABAB receptor expression in the VTA and inhibited METH-induced locomotor sensitization as assessed in the open field test. Moreover, administration of PP2A-Pep into the VTA also reduced drug seeking behavior in the conditioned place preference test. These observations underscore the importance of VTA GABAB receptors in controlling addictive phenotypes. Furthermore, this study illustrates the value of interfering peptides targeting diseases-related protein-protein interactions as an alternative approach for a potential development of selective therapeutic interventions.
摘要：
重复暴露于精神兴奋剂如甲基苯丙胺（METH）诱导神经适应在中皮质边缘多巴胺系统，包括腹侧被盖区（VTA）。这些变化导致持续增强的神经元活性,引起增加的多巴胺释放和成瘾表型。导致该系统中多巴胺能活性增加的因素似乎是VTA中GABAB受体介导的神经元抑制减少。蛋白磷酸酶2A（PP2A）对GABAB2亚基的丝氨酸783（Ser783）的去磷酸化似乎触发了精神兴奋剂成瘾的啮齿动物中GABAB受体的下调。因此,使用干扰肽阻止GABAB受体与PP2A的相互作用是恢复GABAB受体介导的神经元抑制的有前景的策略.我们先前已经开发了抑制GABAB受体/PP2A相互作用并由此在病理条件下恢复受体表达的干扰肽(PP2A-Pep)。这里,我们检验了以下假设:METH成瘾小鼠VTA中GABAB受体表达的恢复减少了成瘾表型。我们发现GABAB受体在METH成瘾小鼠的VTA和伏隔核中的表达显着降低，但在海马和体感皮层中却没有。向METH成瘾小鼠的VTA中输注PP2A-Pep恢复了VTA中GABAB受体的表达，并抑制了METH诱导的运动致敏作用，如在旷场试验中评估的。此外，在条件位置偏好测试中，向VTA中施用PP2A-Pep也减少了药物寻找行为。这些观察结果强调了VTAGABAB受体在控制成瘾表型中的重要性。此外，本研究说明了靶向疾病相关蛋白质-蛋白质相互作用的干扰肽作为选择性治疗干预措施潜在发展的替代方法的价值.
