BDNF-TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms.
BDNF-TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms.
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DOI：
10.1038/tp.2015.157
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发表时间：
2015-10-27
影响因子：
6.8
通讯作者：
Hashimoto K
中科院分区：
文献类型：
--
作者：
Ren Q;Ma M;Yang C;Zhang JC;Yao W;Hashimoto K
在戒酒的头几周里，抑郁是甲基苯丙胺(METH)戒断的核心症状。然而，冰毒戒断症状的确切机制仍不清楚。脑源性神经营养因子(BDNF)及其特异性受体原肌球蛋白相关激酶(TrkB)在抑郁症的病理生理过程中起重要作用。在这项研究中，我们研究了BDNF-TrkB信号在有冰毒戒断症状的雄性小鼠不同脑区中的作用。给小鼠重复给予冰毒(3 mg kg−，每天1次，连续5天)可引起包括快感丧失在内的持久的抑郁样行为。Western印迹分析显示，冰毒处理组小鼠伏隔核(NAC)的BDNF水平显著高于对照组，而其他区域，包括前额叶皮质和海马区的BDNF水平没有改变。随后亚慢性给予TrkB拮抗剂ANA-12(每天0.5 mg kg−1，共14天)，但不给予TrkB激动剂7，8-二羟基黄酮(10 mg kg−1，共14天)，可改善冰毒诱导的抑郁行为、行为敏感化和NAc壳内树突状改变。体内微透析法显示，亚慢性给药后，冰毒(1 mg kg−1)所致小鼠NAc壳多巴胺释放明显减弱。有趣的是，将ANA-12单次注入NAC外壳，而不是NAC核心，显示出快速而持久的治疗效果。然而，氯胺酮和帕罗西汀没有作用。这些结果提示，NAC壳中BDNF-TrkB信号的增加在反复给药后的行为异常中起着重要作用，TrkB拮抗剂是治疗冰毒滥用者戒断症状的潜在药物。
Depression is a core symptom of methamphetamine (METH) withdrawal during the first several weeks of abstinence. However, the precise mechanisms underlying METH withdrawal symptoms remain unknown. Brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), have a role the in pathophysiology of depression. In this study, we examined the role of BDNF–TrkB signaling in different brain regions of male mice with METH withdrawal symptoms. Repeated METH (3 mg kg−1 per day for 5 days) administration to mice caused a long-lasting depression-like behavior including anhedonia. Western blot analysis showed that BDNF levels in the nucleus accumbens (NAc) of METH-treated mice were significantly higher than those of control mice whereas BDNF levels in other regions, including the prefrontal cortex and hippocampus, were not altered. METH-induced depression-like behavior, behavioral sensitization and dendritic changes in the NAc shell were improved by subsequent subchronic administration of TrkB antagonist ANA-12 (0.5 mg kg−1 per day for 14 days), but not TrkB agonist 7,8-dihydroxyflavone (10 mg kg−1 per day for 14 days). In vivo microdialysis showed that METH (1 mg kg−1)-induced dopamine release in NAc shell of METH-treated mice was attenuated after subsequent subchronic ANA-12 administration. Interestingly, a single bilateral infusion of ANA-12 into the NAc shell, but not NAc core, showed a rapid and long-lasting therapeutic effect. However, ketamine and paroxetine had no effect. These findings suggest that increased BDNF–TrkB signaling in the NAc shell has an important role in the behavioral abnormalities after withdrawal from repeated METH administration, and that TrkB antagonists are potential therapeutic drugs for withdrawal symptoms in METH abusers.