IUNICS, University of the Balearic Islands, Palma, Spain.
Balearic Islands Health Research Institute (IdISBa), Palma, Spain.
Addict Biol. 2019 Mar;24(2):239-250. doi: 10.1111/adb.12593. Epub 2017 Dec 28.
While prior studies have established various interacting mechanisms and neural consequences (i.e. monoaminergic nerve terminal damage) that might contribute to the adverse effects caused by methamphetamine administration, the precise mechanisms that mediate relapse during withdrawal remain unknown. This study evaluated the long-term consequences of binge methamphetamine administration (three pulses/day, every 3 hours, 4 days, i.p.; dose-response: 2.5, 5 and 7.5 mg/kg) in adult Sprague-Dawley rats at two behavioral levels following 25 days of withdrawal: (1) negative affect (behavioral despair-forced-swim test, and anhedonia-1% sucrose consumption, two-bottle choice test) and (2) voluntary methamphetamine consumption (20 mg/l, two-bottle choice test). Striatal and hippocampal brain samples were dissected to quantify monoamines content by high-performance liquid chromatography and to evaluate neurotoxicity (dopaminergic and serotonergic markers) and neuroplasticity markers [i.e. cell fate regulator (Fas-associated protein with death domain) FADD] by Western blot. The results showed that methamphetamine administration induced dose-dependent negative effects during prolonged withdrawal in adult rats. In particular, rats treated repeatedly with methamphetamine (7.5 mg/kg) showed (1) enhanced negative affect-increased anhedonia associated with behavioral despair, (2) increased voluntary methamphetamine consumption, (3) enhanced neurotoxicity-decreased dopamine and metabolites in striatum and decreased serotonin in hippocampus, (4) altered neuroplasticity markers-decreased FADD protein and increased p-FADD/FADD balance selectively in hippocampus and (5) higher consumption rates of methamphetamine that were associated with lower FADD content in hippocampus. These results confirm that methamphetamine withdrawal dose-dependently induced negative affect and decreased monoamines content, while also increased voluntary methamphetamine consumption and suggested a role for hippocampal FADD neuroplasticity in these drug-withdrawal adaptations.
虽然先前的研究已经确定了各种相互作用的机制和神经后果（即单胺能神经末梢损伤），这些可能导致冰毒给药的不良影响，但介导戒断期间复发的确切机制仍不清楚。本研究在戒断 25 天后，在两个行为水平上评估了 binge 冰毒给药（3 次/天，每 3 小时，腹腔注射；剂量反应：2.5、5 和 7.5mg/kg）对成年 Sprague-Dawley 大鼠的长期影响：（1）负性情绪（行为绝望-强迫游泳试验和快感缺失-1%蔗糖消耗，双瓶选择试验）和（2）自愿性冰毒消耗（20mg/L，双瓶选择试验）。分离纹状体和海马脑样本，通过高效液相色谱法测定单胺含量，并通过 Western blot 评估神经毒性（多巴胺能和 5-羟色胺能标志物）和神经可塑性标志物[即细胞命运调节剂（死亡域相关 Fas 相关蛋白）FADD]。结果表明，冰毒给药在成年大鼠延长的戒断期间诱导了剂量依赖性的负性影响。具体而言，反复用冰毒（7.5mg/kg）处理的大鼠表现出：（1）负性情绪增强-快感缺失与行为绝望相关，（2）自愿性冰毒消耗增加，（3）神经毒性增强-纹状体中的多巴胺和代谢物减少，海马中的 5-羟色胺减少，（4）神经可塑性标志物改变-海马中 FADD 蛋白减少，p-FADD/FADD 平衡增加，（5）冰毒消耗率增加，与海马中 FADD 含量降低相关。这些结果证实，冰毒戒断剂量依赖性地诱导了负性情绪和单胺含量降低，同时增加了自愿性冰毒消耗，并表明海马 FADD 神经可塑性在这些药物戒断适应中起作用。
