PDF(Pubmed)
Abstract：
Cognitive dysfunction is associated with methamphetamine use disorder (MUD). Here, we used genetic and pharmacological approaches to examine the involvement of either Group 2 metabotropic glutamate (mGlu2) or mGlu3 receptors in memory deficit induced by methamphetamine in mice. Methamphetamine treatment (1 mg/kg, i.p., once a day for 5 d followed by 7 d of withdrawal) caused an impaired performance in the novel object recognition test in wild-type mice, but not in mGlu2-/- or mGlu3-/- mice. Memory deficit in wild-type mice challenged with methamphetamine was corrected by systemic treatment with selectively negative allosteric modulators of mGlu2 or mGlu3 receptors (compounds VU6001966 and VU0650786, respectively). Methamphetamine treatment in wild-type mice caused large increases in levels of mGlu2/3 receptors, the Type 3 activator of G-protein signaling (AGS3), Rab3A, and the vesicular glutamate transporter, vGlut1, in the prefrontal cortex (PFC). Methamphetamine did not alter mGlu2/3-mediated inhibition of cAMP formation but abolished the ability of postsynaptic mGlu3 receptors to boost mGlu5 receptor-mediated inositol phospholipid hydrolysis in PFC slices. Remarkably, activation of presynaptic mGlu2/3 receptors did not inhibit but rather amplified depolarization-induced [3H]-D-aspartate release in synaptosomes prepared from the PFC of methamphetamine-treated mice. These findings demonstrate that exposure to methamphetamine causes changes in the expression and function of mGlu2 and mGlu3 receptors, which might alter excitatory synaptic transmission in the PFC and raise the attractive possibility that selective inhibitors of mGlu2 or mGlu3 receptors (or both) may be used to improve cognitive dysfunction in individuals affected by MUD.
摘要：
认知功能障碍与甲基苯丙胺使用障碍有关。这里,我们使用遗传和药理学方法研究了mGlu2或mGlu3受体在甲基苯丙胺诱导的小鼠记忆缺陷中的作用.甲基苯丙胺治疗（1毫克/千克，i.p.,每天一次，持续5天，然后停药7天）在野生型小鼠的新型物体识别（NOR）测试中导致表现受损，但不在mGlu2-/-或mGlu3-/-小鼠中。用甲基苯丙胺攻击的野生型小鼠的记忆缺陷通过用mGlu2或mGlu3受体的选择性负变构调节剂(分别为化合物VU6001966和VU0650786)进行全身治疗来校正。甲基苯丙胺在野生型小鼠中治疗引起mGlu2/3受体水平的大幅增加，G蛋白信号的3型激活剂（AGS3），Rab3A和囊泡谷氨酸转运体，vGlut1在前额叶皮层（PFC）。甲基苯丙胺不会改变mGlu2/3介导的cAMP形成抑制，但是消除了突触后mGlu3受体促进PFC切片中mGlu5受体介导的肌醇磷脂水解的能力。值得注意的是,突触前mGlu2/3受体的激活没有抑制，而是放大了去极化诱导的[3H]-D-天冬氨酸在由甲基苯丙胺处理的小鼠的PFC制备的突触体中的释放。这些发现表明，暴露于甲基苯丙胺会导致mGlu2和mGlu3受体的表达和功能发生变化，这可能会改变PFC中的兴奋性突触传递，并提出了有吸引力的可能性，即mGlu2或mGlu3受体（或两者）的选择性抑制剂可用于改善受甲基苯丙胺使用障碍影响的个体的认知功能障碍。意义声明针对认知功能障碍可能会减少使用甲基苯丙胺的个体对甲基苯丙胺的渴望和复发。使用新颖的物体识别（NOR）测试来研究识别记忆，我们发现由甲基苯丙胺引起的小鼠认知障碍可以通过mGlu2或mGlu3受体的遗传缺失或选择性药理阻断来纠正。通过抑制谷氨酸释放来控制突触活性的两种代谢型谷氨酸受体亚型。有趣的是,mGlu2/3受体在甲基苯丙胺治疗的小鼠的前额叶皮质中上调，并通过增强去极化诱导的谷氨酸释放显示出相反的操作模式。这些发现表明，选择性mGlu2或mGlu3受体拮抗剂可以改善受甲基苯丙胺使用障碍影响的个体的认知功能。
