Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse
Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse
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DOI：
10.1073/pnas.1011265108
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发表时间：
2011-01-04
影响因子：
11.1
通讯作者：
Kalivas, Peter W.
中科院分区：
文献类型：
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作者：
Moussawi, Khaled;Zhou, Wenhua;Kalivas, Peter W.
可卡因成瘾仍然没有有效的药物治疗，其特征是成瘾者无法抑制吸毒复发。复发的脆弱性源于对动机行为的认知控制的持久损害，部分表现为从前额皮质到丘脑核的投射中的突触增强和细胞外谷氨酸稳态失调。在这里，我们表明，在大鼠训练自我管理可卡因，持久的可卡因诱导的突触增强和谷氨酸稳态的变化是机械地通过II组代谢型谷氨酸受体信号。可卡因引起的皮质-肾上腺皮质激素突触和神经胶质传递的变化在停用胱氨酸前体药物N-乙酰半胱氨酸后至少2周恢复到给药前参数。N-乙酰半胱氨酸通过诱导代谢型谷氨酸受体上的非突触谷氨酸能张力的持久恢复产生这些变化。长期N-乙酰半胱氨酸对可卡因诱导的阿片样物质适应的持久药理学恢复也导致了复发动物模型中可卡因寻求的持久抑制。这些数据机械地链接非突触谷氨酸可卡因诱导的适应兴奋性传输，并证明了一种机制，以慢性恢复前额叶到多巴胺的传输，从而抑制复发的动物模型。
Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N-acetylcysteine. N-acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N-acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaine-induced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model.