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

基本信息

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
项目类别：
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

项目摘要

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障碍之一。由于直接针对单胺、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。一种新颖的治疗方法是破坏与提示相关的记忆有关的神经过程（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）。这些根深蒂固的记忆，当被暗示重新激活时，会引发渴望并重新吸毒。然而，每次线索的重新暴露都需要重新记忆（或重新巩固）药物线索。记忆重新巩固所需的关键分子过程是 NMDA 受体激活、诱导一氧化氮 (NO) 合成和增加细胞外信号调节激酶 (ERK) 活性。在啮齿动物模型中，阻止这些过程会改变与线索相关的记忆；该提示失去了诱导恢复自我给药的效力。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。利多卡因与可卡因一样，是一种局部麻醉剂，具有作为钠通道阻滞剂的有效作用。与可卡因不同，利多卡因基本上缺乏单胺再摄取转运蛋白的活性，并且没有奖励性或成瘾性。由于利多卡因抑制药物线索重新巩固所需的分子过程，并对药物线索重新巩固所需的纹状体区域具有相对特定的影响，因此利多卡因可能提供一种干扰记忆重新巩固的新方法。另外两种 Na+ 通道阻滞剂也可以减少物质依赖受试者的渴望和/或物质使用。在这种治疗可卡因成瘾的概念验证方法中（以我们小组开发的用于评估 PTSD 相关创伤记忆的药理干扰物的范式为模型），将在治疗中评估线索诱导的渴望后输注利多卡因的效果-寻求可卡因成瘾的门诊病人。在诱导线索诱发的渴望后，立即以双盲、随机设计的方式施用利多卡因或盐水。第三组还将在没有提示引起的渴望的情况下评估利多卡因。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。我们建议，相对于盐水加提示诱发的渴望或没有提示诱发的渴望的利多卡因，在诱发提示诱发的渴望后全身施用利多卡因将阻止提示记忆的重新巩固。这将导致重复测试后提示诱发的渴望以及随后的可卡因使用和基础渴望减少。如果我们的假设被证明是正确的，这些发现将 1) 支持利多卡因和可卡因成瘾治疗的作用，2) 证明减弱提示诱发记忆的可行性和有效性，3) 指导利多卡因更大规模研究的开展。