Lidocaine Infusion as a Treatment for Cocaine Relapse and Craving

利多卡因输注治疗可卡因复发和成瘾

• 批准号: 8734362
• 负责人: BRYON H. ADINOFF
• 金额: $ 19.58万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734362
• 关键词: Alcohol dependence; Alcohol or Other Drugs use; Alcohols; Analgesics; Attenuated; Brain region; Clinical; Cocaine; Cocaine Dependence; Cognitive Therapy; Corpus striatum structure; Cues; Development; Disease; Dose; Double-Blind Method; Drug usage; FDA approved; Hour; Human; Individual; Inflammatory; Infusion procedures; Intervention; Lead; Lidocaine; Link; Local Anesthetics; Maintenance; Measures; Mediating; Memory; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monitor; N-Methyl-D-Aspartate Receptors; Neuropathy; Nicotine Dependence; Nitric Oxide; Nucleus Accumbens; Opiate Addiction; Opioid; Outpatients; Pain; Patients; Persons; Pharmaceutical Preparations; Physiological; Post-Traumatic Stress Disorders; Postoperative Pain; Pre-Clinical Model; Preclinical Drug Evaluation; Process; Production; Property; Randomized; Receptor Activation; Relapse; Relative (related person); Rewards; Rodent; Rodent Model; Role; Saline; Self Administration; Sensory Receptors; Societies; Sodium Channel Blockers; Status Epilepticus; Stimulus; Substance Use Disorder; Synaptic plasticity; Testing; Therapeutic Effect; Trauma; Treatment outcome; Urine; addiction; arm; channel blockers; cocaine use; cost; craving; cytokine; design; lamotrigine; monoamine; novel; novel strategies; painful neuropathy; pre-clinical; preference; public health relevance; relating to nervous system; response; uptake

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.

描述（由申请人提供）：可卡因依赖性是药物使用障碍中最顽强的依赖性之一，但仍然是缺乏有效的药理干预措施的少数人之一。由于药理方法直接靶向单胺，GABA能和NMDA受体并非富有成果（2），因此需要新的靶标。一种新的治疗方法是破坏与提示相关记忆中涉及的神经过程（与药物使用相关的外部刺激与主观药物效应之间的记忆联系）。这些内心的记忆被提示重新激活时，引起了渴望和返回吸毒。但是，每个提示重新暴露都需要对药物提示的重新记忆（或重新固定）。记忆重新溶解所需的关键分子过程是NMDA受体激活，一氧化氮（NO）合成的诱导和增加细胞外信号调节激酶（ERK）活性。在啮齿动物模型中，阻止这些过程改变了与提示相关的内存。该提示失去了诱发毒品自我管理的效力。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（Lidocaine）像可卡因一样，是一种局部麻醉剂，作为钠通道阻滞剂具有有效作用。与可卡因不同，利多卡因基本上没有单胺再摄取转运蛋白的活性，并且没有有意义或上瘾的特性。由于利多卡因抑制了药物提示重新溶解所需的分子过程，并且对药物提示重新溶解所需的纹状体区域具有相对特异性的影响，利多卡因可能会提供一种新的方法来干扰记忆重新溶解的方法。其他两个NA+通道阻滞剂也减少了依赖物质受试者的渴望和/或物质使用。在这种治疗可卡因成瘾的概念概念方法中（以我们小组为评估PTSD与PTSD相关的创伤记忆的药理学破坏者开发的范式建模），在提示诱发的抗scre抗病后，将在寻求治疗的治疗方法中评估lidocaine Infusion的效果。在引起提示引起的渴望之后，利多卡因或盐水将立即以双盲，随机的设计给药。在没有提示引起的渴望的情况下，第三臂还将评估利多卡因。输注后一周，将评估提示引起的渴望。可卡因的使用和渴望（非提示引起的）将被监测四个星期。我们提出，相对于盐水加上提示引起的渴望或没有提示引起的渴望的提示引起的渴望或利多卡因，在诱导提示引起的渴望之后，全身给药会阻止提示记忆的重新整理。这将导致在重复测试以及随后的可卡因使用和基础渴望时减少提示引起的渴望。如果我们的假设被证明是正确的，这些发现将1）支持利多卡因和可卡因成瘾治疗的作用，2）证明了减弱提示诱发的记忆的可行性和功效，以及3）指导使用Lidocaine进行更大的研究。