Identifying topiramate's therapeutic mechanisms through motivational salience

描述(申请人提供)：抗惊厥托吡酯(TPM)已被成功地用作治疗药物滥用的药物，包括酒精和尼古丁依赖，但确切的治疗机制尚不清楚。这项建议的目的是通过使用事件相关电位(ERP)测量来确定TPM的可能治疗机制，参与者被招募为目前资助的治疗酒精依赖吸烟者的多部位安慰剂对照临床试验的一部分。作为父母资助的一部分，参与者将被随机接受安慰剂、低剂量TPM(每天最高125毫克)或高剂量TPM(每天最高250毫克)，以及简短的行为依从性增强治疗，以防止再次吸烟和酗酒。对于这项建议，德克萨斯大学MD Anderson癌症中心网站的参与者(n=123；父母赠款n=78，这项建议n=45)将完成两项实验室ERP评估，这两项评估与基线(服药前1周，戒烟前6周)和戒烟前(服药5周，戒烟前1周)的临床就诊情况一致。这些评估将包括在呈现与毒品相关的图片(酒精和香烟线索)、情绪(愉快和不愉快)和中性内容的图片期间记录的密集阵列ERP(129个传感器)。晚期正电位(LPP)的ERP成分将为我们提供一种中枢神经系统测量图片的激励性突显的方法。本研究的第一个具体目的是通过评估TPM对药物相关和情绪线索的动机突显的影响来确定TPM的治疗机制，第二个目标是确定TPM在戒毒后对药物使用、强化、渴望和戒断的影响的治疗机制。这个项目的意义和影响有三个方面：1)这将是 第一项研究旨在评估TPM治疗酒精依赖吸烟者的可能治疗机制，2)提出的用于确定治疗机制的生物标记物，LPP ERP动机突显测量，可用于确定哪些酒精依赖吸烟者可能从TPM中受益，以及3)该生物标记物可用于确定其他药物依赖治疗的可能治疗机制以及那些可能从中受益的人。我们预计，我们的数据将对完善目前的药物成瘾模型产生积极影响，并将从根本上提高我们对尼古丁成瘾所涉及的神经生物学过程的了解。

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.