伏隔核壳部巴氯芬灌注阻断吗啡成瘾小鼠条件位置性偏爱记忆再巩固

Intra-nucleus accumbens shell injection of baclofen blocks the reconsolidation of conditioned place preference in morphine-addicted mice

氨基丁酸B型受体(GABAB受体)是治疗药物成瘾的潜在靶点,伏隔核壳部(nucleus accumbens shell, AcbSh)是成瘾环路的关键节点,但AcbSh GABA_B受体与记忆再巩固的关系尚不清楚。本文旨在探讨AcbSh微量灌注GABA_B受体激动剂巴氯芬(baclofen, BLF)对吗啡奖赏记忆再巩固及复吸行为的影响。建立吗啡条件位置性偏爱(conditioned place preference, CPP)小鼠模型,采用吗啡奖赏记忆提取激活实验,对比观察环境线索激活吗啡奖赏记忆后,双侧AcbSh灌注BLF对吗啡CPP、吗啡激发CPP重建以及自主活动量的影响。结果表明,吗啡奖赏记忆激活后,Acb Sh单次注入0.06nmol/0.2μL/侧或0.12nmol/0.2μL/侧BLF显著抑制吗啡CPP,且吗啡激发不能重建CPP,而0.01nmol/0.2μL/侧BLF灌注不能抑制吗啡CPP。激活后注入生理盐水及未激活组BLF灌注均未抑制CPP。无论是否激活吗啡奖赏记忆,BLF注入AcbSh都不影响小鼠自主活动。以上结果提示,AcbSh GABA_B受体参与了吗啡CPP的记忆再巩固。记忆激活后激动AcbSh GABA_B受体可通过阻断吗啡CPP的记忆再巩固,消除奖赏记忆,抑制复吸行为。

Preclinical studies suggest that the GABA_B receptor is a potential target for treatment of substance use disorders.Baclofen(BLF),a prototypical GAB AB receptor agonist,is the only specific GAB AB receptor agonist available for application in clinical addiction treatment.The nucleus accumbens shell(AcbSh) is a key node in the circuit that controls reward-directed behavior.However,the relationship between GAB AB receptors in the AcbSh and memory reconsolidation was unclear.The aim of this study was to investigate the effect of intra-AcbSh injection of BLF on the reconsolidation of morphine reward memory.Male C57BL/6J mice were used to establish morphine conditioned place preference(CPP) model and carry out morphine reward memory retrieval and activation experiment.The effects of intra-Acb Sh injection of BLF on morphine-induced CPP,reinstatement of CPP and locomotor activity were observed after environmental cues activating morphine reward memory.The results showed that intra-AcbSh injection of BLF(0.06 nmol/0.2 μL/side or 0.12 nmol/0.2 μL/side),rather than vehicle or BLF(0.01 nmol/0.2 μL/side),following morphine reward memory retrieval abolished morphine-induced CPP by disrupting its reconsolidation in mice.Moreover,this effect persisted for more than 14 days,which was not reversed by a morphine priming injection.Furthermore,intra-AcbSh injection of BLF without morphine reward memory retrieval had no effect on morphine-associated reward memory.Interestingly,administration of BLF into the AcbSh had no effect on the locomotor activity of mice during testing phase.Based on these results,we concluded that intra-AcbSh injection of BLF following morphine reward memory could erase morphine-induced CPP by disrupting its reconsolidation.Activating GAB AB receptor in AcbSh during drug memory reconsolidation may be a potential approach to prevent drug relapse.