Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse
Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse
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DOI：
10.1038/nn1069
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发表时间：
2003-07-01
影响因子：
25
通讯作者：
Kalivas, PW
中科院分区：
文献类型：
--
作者：
Baker, DA;McFarland, K;Kalivas, PW
反复的可卡因治疗和戒断会导致大脑功能的变化，这种变化被认为与药物使用的复发有关。从重复可卡因的撤回减少在体内细胞外谷氨酸在大鼠延髓核通过减少细胞外胱氨酸的细胞内谷氨酸的交换。通过颅内灌注胱氨酸或全身给予N-乙酰半胱氨酸恢复体内胱氨酸/谷氨酸交换使可卡因治疗受试者的谷氨酸水平正常化。为了确定非囊泡谷氨酸释放的减少是否是复发的介质，我们研究了可卡因引发的可卡因自我给药停止后药物寻求的恢复。通过用N-乙酰半胱氨酸刺激胱氨酸/谷氨酸交换和恢复细胞外谷氨酸来防止恢复。因此，从重复可卡因戒断增加复发的易感性部分通过减少胱氨酸/谷氨酸交换，并恢复交换活性防止可卡因引发的药物寻求。
Repeated cocaine treatment and withdrawal produces changes in brain function thought to be involved in relapse to drug use. Withdrawal from repeated cocaine reduced in vivo extracellular glutamate in the nucleus accumbens of rats by decreasing the exchange of extracellular cystine for intracellular glutamate. In vivo restoration of cystine/glutamate exchange by intracranial perfusion of cystine or systemically administered N-acetylcysteine normalized the levels of glutamate in cocaine-treated subjects. To determine if the reduction in nonvesicular glutamate release is a mediator of relapse, we examined cocaine-primed reinstatement of drug seeking after cocaine self-administration was stopped. Reinstatement was prevented by stimulating cystine/glutamate exchange with N-acetylcysteine and restoring extracellular glutamate. Thus, withdrawal from repeated cocaine increases susceptibility to relapse in part by reducing cystine/glutamate exchange, and restoring exchanger activity prevents cocaine-primed drug seeking.