【作者】 常海刚； 马鹏举； 杨卫泷； 李祥生； 刁玉岭； 惠磊；

【机构】 新乡医学院第一附属医院神经外科；

【摘要】 背景:岛叶是内感受神经中枢,也是药物成瘾神经环路的关键神经底物,脑深部电刺激是调节特定脑区神经元活性的可逆、微创伤神经外科措施,已逐渐成为难治性神经精神疾病的一种手段。目的:最新研究表明,干预操控岛叶活性是治疗药物成瘾的很有希望的一个靶区,DBS是一种很有效的神经调控技术。设计本实验的目的是探究前岛叶持续高频DBS在吗啡成瘾动物模型的疗效。方法:大鼠被训练成吗啡-条件化位置偏爱(10mg/Kg,两天1次,共4次),并于双侧前岛叶植入DBS。在戒断阶段前14天持续给予高频电刺激(130Hz,150μA,90μs),并于戒断第1天、第15天和25天进行CPP测试。在消退阶段持续给予高频电刺激(130Hz,150μA,90μs)。消退阶段第5天进行CPP测试。在完全消退后,通过吗啡点燃剂量(2 mg/kg)注射恢复吗啡位置偏爱并立即行CPP测试。结果:在戒断15天,持续高频DBS显著降低了吗啡-位置偏爱的表达,而停止电刺激10天后于戒断后25天恢复了吗啡-位置偏爱。在吗啡CPP消退期,持续HF-DBS加快促进吗啡位置偏爱完全消退并且阻止了吗啡点燃诱导的吗啡位置偏爱复发。前岛叶持续高频DBS对运动活动能力及自然奖赏没有影响,对新物体识别记忆无明显损害也不引起焦虑。结论:综合目前的数据结果表明,双侧前岛叶持续高频电刺激有效缓解了药物戒断15天后吗啡成瘾样行为的复发,而停止DBS后,治疗效应减弱。同时双侧前岛叶持续高频电刺激促进吗啡偏爱的消退,并阻止药物点燃诱导的吗啡寻求行为的恢复。这些发现为治疗难治性药物成瘾探索新靶区和DBS作为一种有希望的潜在干预措施提供了实验证据,需要进一步研究来评估其在临床转化价值。更多还原

【Abstract】 Backgroud:Insula is central hub of interoception,and also the critical neurosubstrate of drug addiction.Deep brain stimulation(DBS) used to modulate the neuron activity in specific brain circuits,has emerged as a promising non-drug therapy to treatment-refractory addiction.Objective:Recent research demonstrates that manipulation of insula activity plays a therapeutic effect in drug addiction.The object of this experiments was to determine long-term efficiency and safety of non-intermittent high frequency DBS of anterior insula in morphine addictive animals.Methods:Rats underwent 8-day drug pairing schedule(10mg/Kg) were trained to the morphine-conditioned place preference(CPP) and subsequently bilaterally implanted with DBS electrodes in the anterior insula(AI).Non-intermittent high-frequency(HF;130Hz,150μA,90μs) DBS was applied during withdrawal(14 consecutive days from day 1 to day 15 during drug withdrawal phase) or extinction sessions.CPP tests were conducted on days 1,15,25 during withdraw session.Following absolute extinction,morphine-CPP was reinstated by a priming dose of morphine infusion(2mg/Kg) and CPP test was performed immediately.Results:Non-intermittent high-frequency DBS of AI attenuated expression of morphine-CPP on day 15 post-withdraw,but morphine addictive behavior relapsed on day 25 ten days after interruption/cessation of DBS.Non-intermittent high-frequency DBS advanced full extinction of morphine-CPP and blocked morphine priming-induced recurrence of morphine addiction.The pattern of DBS had no effect on locomotor activity,and had no obvious damage to novel object recognition memory and caused no anxiety.Conclusion:The results showed that non-intermittent high-frequency DBS of AI alleviated the relapse of morphine addictive behavior after 15 days of drug withdrawal,with diminished therapeutic efficiency after DBS interruption,and strengthened extinction and prevented the priming-induced reinstatement of morphine seeking.These findings provide support for the exploration of new targets for the treatment of refractory drug addiction and suggest that AI DBS mimics an inactivation of insula on interoceptive processes.Further research is needed to evaluate its clinical transformation value.更多还原