Drug-Induced Plasticity Contributing to Heightened Relapse Susceptibility: Neurochemical Changes and Augmented Reinstatement in High-Intake Rats
Drug-Induced Plasticity Contributing to Heightened Relapse Susceptibility: Neurochemical Changes and Augmented Reinstatement in High-Intake Rats
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DOI：
10.1523/jneurosci.1342-09.2010
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发表时间：
2010-01-06
影响因子：
5.3
通讯作者：
Baker, David A.
中科院分区：
文献类型：
--
作者：
Madayag, Aric;Kau, Kristen S.;Baker, David A.
了解成瘾的神经生物学和开发有效药物治疗的关键是揭示药物诱导的可塑性，导致复发易感性增加。先前的研究表明，伏隔核（NAcc）细胞外谷氨酸的增加，而不是多巴胺的增加，是可卡因诱导的恢复所必需的。在本报告中，我们研究了产生可卡因诱导的恢复所必需的药物诱导适应是否也决定了复发易感性。为了做到这一点，大鼠被分配在低（2小时/天；0.5 mg/kg/输注，静脉注射）或高（6小时/天；1.0 mg/kg/输注，静脉注射）药物摄入水平的条件下自我施用可卡因，因为这些操作产生的大鼠组在可卡因诱导的恢复程度上表现出差异。在最后一次治疗后约19 d，测量了可卡因诱导的药物寻找和NAcc中谷氨酸和多巴胺的细胞外水平。与我们的假设相反，高摄入量的大鼠表现出更强的可卡因诱导的细胞外多巴胺水平的增加，而不是谷氨酸。此外，当将D-1受体拮抗剂SCH-23390输注到NAcc中时，高摄入量大鼠的恢复不再增加。高摄入量大鼠对可卡因的致敏多巴胺反应可能涉及系统x(c)-的胱氨酸-谷氨酸交换钝化。在高摄入量大鼠的NAcc组织切片中，通过x系统(c)-摄取的c -14-胱氨酸明显减少，当受试者接受半胱氨酸前药n -乙酰半胱氨酸时，这些大鼠的多巴胺反应不再增强。这些数据揭示了药物诱导的NAcc多巴胺在高水平药物摄入史大鼠中观察到的复发易感性增加中的作用。
A key in understanding the neurobiology of addiction and developing effective pharmacotherapies is revealing drug-induced plasticity that results in heightened relapse susceptibility. Previous studies have demonstrated that increased extracellular glutamate, but not dopamine, in the nucleus accumbens core (NAcc) is necessary for cocaine-induced reinstatement. In this report, we examined whether drug-induced adaptations that are necessary to generate cocaine-induced reinstatement also determine relapse vulnerability. To do this, rats were assigned to self-administer cocaine under conditions resulting in low ( 2 h/d; 0.5 mg/kg/infusion, i.v.) or high ( 6 h/d; 1.0 mg/kg/infusion, i.v.) levels of drug intake since these manipulations produce groups of rats exhibiting differences in the magnitude of cocaine-induced reinstatement. Approximately 19 d after the last session, cocaine-induced drug seeking and extracellular levels of glutamate and dopamine in the NAcc were measured. Contrary to our hypothesis, high-intake rats exhibited a more robust cocaine-induced increase in extracellular levels of dopamine but not glutamate. Further, increased reinstatement in high-intake rats was no longer observed when the D-1 receptor antagonist SCH-23390 was infused into the NAcc. The sensitized dopamine response to cocaine in high-intake rats may involve blunted cystine-glutamate exchange by system x(c)-. Reduced C-14-cystine uptake through system x(c)- was evident in NAcc tissue slices obtained from high-intake rats, and the augmented dopamine response in these rats was no longer observed when subjects received the cysteine prodrug N-acetyl cysteine. These data reveal a role for drug-induced NAcc dopamine in heightened relapse vulnerability observed in rats with a history of high levels of drug intake.