Identifying topiramate's therapeutic mechanisms through motivational salience

通过动机显着性识别托吡酯的治疗机制

• 批准号: 8399466
• 负责人: Jason D Robinson
• 金额: $ 25.42万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399466
• 关键词: Alcohol dependence; Alcohols; Anti-Anxiety Agents; Anticonvulsants; Behavioral; Biological Markers; Cigarette; Clinical; Controlled Clinical Trials; Cues; Data; Dependence; Dopamine; Dose; Drug Addiction; Drug usage; Emotional; Event-Related Potentials; Funding; Glutamate Receptor; Heavy Drinking; Individual; Knowledge; Laboratories; Measures; Mediating; Modeling; Neuraxis; Neurobiology; Nicotine Dependence; Outcome Study; Participant; Pharmaceutical Preparations; Pharmacological Treatment; Placebo Control; Placebos; Process; Property; Psychological reinforcement; Randomized; Recruitment Activity; Relapse; Rewards; Sedation procedure; Site; Smoker; Smoking; Stimulus; Substance Addiction; Therapeutic; Therapeutic Agents; Treatment outcome; University of Texas M D Anderson Cancer Center; Visit; Withdrawal; Work; addiction; alcohol abuse therapy; craving; drug of abuse; drug withdrawal; experience; gamma-Aminobutyric Acid; innovation; neurotransmission; parent grant; prevent; relating to nervous system; sedative; sensor; substance abuse treatment; topiramate

DESCRIPTION (provided by applicant): The anticonvulsive topiramate (TPM) has been successfully used as a therapeutic agent for the treatment of substance abuse, including alcohol and nicotine dependence, but the precise therapeutic mechanisms are unknown. The objective of this proposal is to determine the likely therapeutic mechanism of TPM by using event-related potential (ERP) measures, with participants recruited as part of a currently funded multisite placebo-controlled clinical trial treating alcohol-dependent smokers. As part of the parent grant, participants will be randomized to receive placebo, low-dose TPM (up to 125 mg/day), or high-dose TPM (up to 250 mg/day), along with brief behavioral compliance enhancement treatment, to prevent relapse to smoking and heavy drinking. For this proposal, participants (n=123; parent grant n=78, this proposal n=45) at The University of Texas MD Anderson Cancer Center site will complete two laboratory ERP assessments that coincide with clinical visits at baseline (1 week pre-medication, 6 weeks pre-quit) and pre-quit (5 weeks on medication, 1 week pre-quit). These assessments will consist of dense-array ERPs (129 sensors) recorded during the presentation of pictures with drug-related (alcohol and cigarette cues), emotional (pleasant and unpleasant), and neutral content. The late positive potential (LPP) ERP component will provide us with a central nervous system measure of motivational salience of the pictures. The first specific aim of this study is to identify TPM's therapeutic mechanism by evaluating its impact on the motivational salience of drug-related and emotional cues, and the second aim is to determine which therapeutic mechanism mediates the impact of TPM on post-quit drug use, reinforcement, craving, and withdrawal. The significance and impact of this project are threefold: 1) this will be the first study to evaluate the likely therapeutic mechanisms of TPM in the treatment of alcohol-dependent smokers, 2) the proposed biomarker for identifying therapeutic mechanisms, LPP ERP measures of motivational salience, could be used to identify which alcohol-dependent smokers are likely to benefit from TPM, and 3) this biomarker could be used to identify the likely therapeutic mechanisms of other pharmacological treatments of substance dependence and those who would likely benefit from them. We anticipate that our data will have a positive impact by contributing to the refinement of current models of drug addiction and will fundamentally advance our knowledge of the neurobiological processes involved in nicotine addiction. PUBLIC HEALTH RELEVANCE: This proposal will be the first to investigate the likely therapeutic mechanisms of the medication topiramate in the treatment of alcohol-dependent smokers and to identify those who would likely benefit from this promising treatment of alcohol and nicotine dependence. Understanding how this new treatment works and who would likely benefit from it could help more alcohol-dependent smokers become addiction-free.

描述（申请人提供）：抗惊厥托吡酯（TPM）已成功用作药物滥用的治疗剂，包括酒精和尼古丁依赖，但确切的治疗机制尚不清楚。该提案的目的是通过使用事件相关电位 (ERP) 测量来确定 TPM 可能的治疗机制，招募参与者作为目前资助的治疗酒精依赖吸烟者的多中心安慰剂对照临床试验的一部分。作为家长资助的一部分，参与者将被随机接受安慰剂、低剂量 TPM（高达 125 毫克/天）或高剂量 TPM（高达 250 毫克/天），以及简短的行为依从性增强治疗，以防止复发吸烟和酗酒。对于该提案，德克萨斯大学 MD 安德森癌症中心的参与者（n=123；家长资助 n=78，本提案 n=45）将完成两项实验室 ERP 评估，这些评估与基线（用药前 1 周，戒烟前 6 周）和戒烟前（用药 5 周，戒烟前 1 周）的临床访视一致。这些评估将包括在展示与药物相关（酒精和香烟线索）、情绪（愉快和不愉快）和中性内容的图片时记录的密集阵列 ERP（129 个传感器）。晚期正电位 (LPP) ERP 组件将为我们提供中枢神经系统对图片动机显着性的测量。本研究的第一个具体目标是通过评估 TPM 对药物相关和情绪线索的动机显着性的影响来确定 TPM 的治疗机制，第二个目标是确定哪种治疗机制介导 TPM 对戒烟后药物使用、强化、渴望和戒断的影响。该项目的意义和影响有三重：1) 第一项评估 TPM 在治疗酒精依赖型吸烟者中可能的治疗机制的研究，2）拟议的用于识别治疗机制的生物标志物，LPP ERP 动机显着性测量，可用于识别哪些酒精依赖型吸烟者可能从 TPM 中受益，3）该生物标志物可用于识别物质依赖和其他药物治疗的可能治疗机制。 那些可能从中受益的人。我们预计我们的数据将有助于完善当前的药物成瘾模型，从而产生积极的影响，并将从根本上增进我们对尼古丁成瘾所涉及的神经生物学过程的了解。 公共健康相关性：该提案将首次研究托吡酯药物治疗酒精依赖吸烟者的可能治疗机制，并确定那些可能从这种有希望的酒精和尼古丁依赖治疗方法中受益的人。了解这种新疗法的作用原理以及谁可能从中受益，可以帮助更多依赖酒精的吸烟者戒除酒精成瘾。