Lidocaine Infusion as a Treatment for Cocaine Relapse and Craving

描述（由申请人提供）：可卡因依赖是最顽固的物质使用障碍之一，但仍然是少数缺乏有效药理干预的疾病之一。由于直接靶向单胺、GABAergic和NMDA受体的药理学方法尚未取得成果(2)，因此需要新的靶点。一种新的治疗方法是破坏线索相关记忆（与药物使用相关的外部刺激和主观药物效应之间的记忆联系）的神经过程。当这些根深蒂固的记忆被线索重新激活时，就会引发渴望和再次吸毒。然而，每次线索再暴露都需要对药物线索的重新记忆（或重新巩固）。记忆再巩固所需的关键分子过程是NMDA受体激活、一氧化氮（NO）合成的诱导和细胞外信号调节激酶（ERK）活性的增加。在啮齿动物模型中，阻断这些过程会改变线索相关的记忆；这种暗示失去了诱导患者重新自我服药的效力。利多卡因是FDA批准的药物，可抑制NMDA受体的激活并抑制NO和ERK的产生。利多卡因和可卡因一样，是一种局部麻醉剂，作为钠通道阻滞剂具有强大的作用。与可卡因不同，利多卡因基本上缺乏单胺再摄取转运体的活性，没有奖励或成瘾特性。由于利多卡因抑制药物线索再巩固所需的分子过程，并且对药物线索再巩固所需的纹状体区域具有相对特异性的影响，利多卡因可能为干扰记忆再巩固提供一种新的途径。另外两种钠离子通道阻滞剂也能减少物质依赖患者的渴望和/或物质使用。在这个治疗可卡因成瘾的概念验证方法中（以我们小组开发的评估ptsd相关创伤记忆的药理学干扰物的范例为模型），利多卡因输注在线索诱导的渴望后的效果将在寻求治疗的可卡因成瘾门诊患者中进行评估。在诱导线索诱导的渴望后，立即给予利多卡因或生理盐水，采用双盲随机设计。第三组还将评估利多卡因在没有线索诱导的渴望的情况下。注射一周后，将评估提示诱导的渴望。可卡因的使用和渴望（非线索诱导）将被监测四周。我们认为，与生理盐水加线索诱导的渴望或利多卡因不加线索诱导的渴望相比，在线索诱导的渴望诱导后全身给予利多卡因会阻止线索记忆的再巩固。这将导致在重复测试中线索诱导的渴望以及随后的可卡因使用和基础渴望的减少。如果我们的假设被证明是正确的，这些发现将1)支持利多卡因在可卡因成瘾治疗中的作用，2)证明减弱线索诱导记忆的可行性和有效性，以及3)指导利多卡因更大规模研究的发展。

DESCRIPTION (provided by applicant): Cocaine dependence is among the most tenacious of the substance use disorders yet remains one of the few lacking an effective pharmacological intervention. As pharmacologic approaches directly targeting monoamine, GABAergic, and NMDA receptors have not been fruitful (2), new targets are required. A novel treatment approach is to disrupt the neural processes involved in cue-related memories (memory links between the external stimuli associated with drug use and the subjective drug effect). These engrained memories, when reactivated by cues, elicit craving and a return to drug use. Each cue re-exposure, however, requires the re- remembering (or reconsolidation) of the drug cue. Key molecular processes required for memory reconsolidation are NMDA receptor activation, the induction of nitric oxide (NO) synthesis and increased extracellular signal-regulated kinase (ERK) activity. In rodent models, blocking these processes changes the cue-related memory; the cue loses its potency to induce a return to drug self-administration. Lidocaine is an FDA approved medication that inhibits activation of NMDA receptors and suppresses production of NO and ERK. Lidocaine, like cocaine, is a local anesthetic with potent effects as a sodium-channel blocker. Unlike cocaine, lidocaine is essentially devoid of activity at monoamine re-uptake transporters and has no rewarding or addictive properties. As lidocaine suppresses the molecular processes required for drug cue reconsolidation and has relatively specific effects upon the striatal regions necessary for drug cue reconsolidation, lidocaine may offer a novel approach for interfering with memory reconsolidation. Two other Na+ channel blockers have also decrease craving and/or substance use in substance-dependent subjects. In this proof-of-concept approach for the treatment of cocaine addiction (modeled on a paradigm developed by our group to assess pharmacologic disruptors of PTSD-related trauma memories), the effect of lidocaine infusion following cue- induced craving will be assessed in treatment-seeking, cocaine-addicted outpatients. Immediately following the induction of cue-induced craving, lidocaine or saline will be administered in a double-blind, randomized design. A third arm will also assess lidocaine in the absence of cue-induced craving. One week following the infusion, cue-induced craving will be assessed. Cocaine use and craving (non cue-induced) will be monitored for four weeks. We propose that the systemic administration of lidocaine following the induction of cue-induced craving, relative to saline plus cue-induced craving or lidocaine without cue-induced craving will block the reconsolidation of cue memories. This will lead to a reduction in cue-induced craving upon repeated testing as well as subsequent cocaine use and basal craving. If our hypotheses are proven correct, these findings will 1) support a role for lidocaine n cocaine addiction treatment, 2) demonstrate the feasibility and efficacy of attenuating cue-induced memories, and 3) guide the development of a larger study with lidocaine.