Identifying topiramate's therapeutic mechanisms through motivational salience

描述（由申请人提供）：抗惊厥托吡酯（TPM）已被成功地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。本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，参与者是目前资助的治疗酒精依赖吸烟者的多地点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），以及短暂的行为依从性增强治疗，以防止吸烟和酗酒复发。在本方案中，在德克萨斯大学MD安德森癌症中心的参与者（n=123；家长资助n=78，本方案n=45）将完成两项实验室ERP评估，同时在基线（服药前1周，戒烟前6周）和戒烟前（服药5周，戒烟前1周）进行临床访问。这些评估将包括密集排列的erp（129个传感器），在呈现与毒品相关（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。后期正电位（LPP） ERP成分将为我们提供中枢神经系统对图像动机显著性的测量。本研究的第一个具体目的是通过评估TPM对药物相关线索和情绪线索的动机显著性的影响来确定其治疗机制，第二个目的是确定哪种治疗机制介导TPM对戒断后药物使用、强化、渴望和戒断的影响。这个项目的意义和影响有三个方面：1)这将是

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.