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物干预的疾病之一。由于直接靶向单胺、GABA能和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与线索相关记忆（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）有关的神经过程。这些根深蒂固的记忆，当被线索重新激活时，会引起渴望和重新使用毒品。然而，每一个线索的重新暴露都需要重新记住（或重新巩固）药物线索。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;线索失去了诱导恢复自我给药的效力。利多卡因是一种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，像可卡因一样，是一种局部麻醉剂，具有强效钠通道阻滞剂的作用。与可卡因不同，利多卡因基本上不具有单胺再摄取转运蛋白的活性，并且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，并对药物线索再巩固所需的纹状体区域具有相对特异性的作用，利多卡因可能提供一种新的方法来干扰记忆再巩固。另外两种Na+通道阻滞剂也降低了物质依赖性受试者的渴望和/或物质使用。在这种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），将在寻求治疗的可卡因成瘾门诊患者中评估线索诱导的渴望后利多卡因输注的效果。在诱导线索诱导的渴望后，立即以双盲、随机设计给予利多卡因或生理盐水。第三组也将在没有线索诱导的渴望的情况下评估利多卡因。输注后一周，将评估线索诱导的渴望。将对可卡因使用和渴望（非线索诱导）进行为期四周的监测。我们认为，相对于生理盐水加线索诱发的渴求或利多卡因无线索诱发的渴求，线索诱发的渴求诱导后全身给予利多卡因会阻断线索记忆的再巩固。这将导致在重复测试时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，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.