Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin 53233, USA.
J Neurosci. 2010 Jan 6;30(1):210-7. doi: 10.1523/JNEUROSCI.1342-09.2010.
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 (14)C-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.
理解成瘾的神经生物学和开发有效的药物治疗方法的关键是揭示导致复发易感性增加的药物诱导可塑性。先前的研究表明，伏隔核核心（NAcc）中细胞外谷氨酸的增加，而不是多巴胺的增加，是可卡因诱导复吸所必需的。在本报告中，我们检查了产生可卡因诱导复吸所必需的药物诱导适应是否也决定了复发易感性。为此，将大鼠分配到在导致低（2 小时/天；0.5 mg/kg/次，静脉内）或高（6 小时/天；1.0 mg/kg/次，静脉内）药物摄入水平下自我给药可卡因，因为这些操作产生了显示可卡因诱导复吸程度差异的大鼠组。在最后一次疗程后约 19 天，测量了 NAcc 中的可卡因诱导药物寻求和细胞外谷氨酸和多巴胺水平。与我们的假设相反，高摄入大鼠表现出更强的可卡因诱导的细胞外多巴胺水平增加，但谷氨酸水平没有增加。进一步，当将 D1 受体拮抗剂 SCH-23390 注入 NAcc 时，高摄入大鼠的复吸增加不再观察到。高摄入大鼠中对可卡因的敏化多巴胺反应可能涉及系统 x(c(-))的胱氨酸-谷氨酸交换减弱。从高摄入大鼠获得的 NAcc 组织切片中明显存在通过系统 x(c(-))减少的（14）C-胱氨酸摄取，并且当给予半胱氨酸前体 N-乙酰半胱氨酸时，这些大鼠中增强的多巴胺反应不再观察到。这些数据揭示了药物诱导的 NAcc 多巴胺在高摄入大鼠中观察到的复发易感性增加中的作用。
