Dismantling MBRP: Identifying Critical Neuroimmune Mechanisms of Action

 描述（由申请人提供）：最近的研究表明，多巴胺基因的表观遗传调控是奖赏回路适应性的重要分子机制。一些研究还表明，免疫系统的扰动导致神经炎症是执行控制网络连接变化的重要机制。这两个因素都是导致酒精使用障碍的病因和维持的机制。许多研究表明，基于正念的干预可以减少炎症（即，神经炎症）并影响表观遗传调节。最后，基于正念的复发预防（MBRP）最近在治疗物质使用障碍方面表现出了疗效，尽管目前还不清楚MBRP是如何工作的。在拟议研究的第一个目标中，MBRP的正念成分将通过比较MBRP干预与复发预防（RP）干预的效果从复发预防成分中分离出来，从而隔离正念效果。在第二个目标中，拟议的研究将通过测试干预对炎症生物标志物（IL-6，IL-8和TNFα）的影响以及MBRP对关键基因（DRD 2，SLC 6A 3，DBH）的表观遗传调控的影响来检查可能介导MBRP效应的机制。此外，拟议的工作将研究干预对奖励系统的神经功能以及大脑执行控制网络的连接的影响。在目标3中，该研究将确定MBRP对免疫系统功能和表观遗传调节的影响是否介导MBRP对治疗结果的影响。为此，226例患者将随机接受8周MBRP或RP治疗。将在第4周和第8周测定推定的介质。将在第4、8、20（治疗结束后12周）和32周（治疗结束后24周）评估饮酒结果。这项研究的成功完成预计将具有重大的临床和科学意义。

 DESCRIPTION (provided by applicant): Recent work suggests that the epigenetic regulation of dopamine genes is an important molecular mechanism underlying adaptations in reward circuits. Several studies have also indicated that perturbations in the immune system leading to neuroinflammation is an important mechanism underlying changes in the connectivity of executive control networks. Both of these factors are mechanisms that putatively underlie the etiology and maintenance of alcohol use disorders. A number of studies indicate that mindfulness based interventions may reduce inflammation (i.e., neuroinflammation) and influence epigenetic regulation. Finally, Mindfulness Based Relapse Prevention (MBRP) has recently demonstrated efficacy in the treatment of substance use disorders, although it is not clear how MBRP works. In the first aim of the proposed research, the mindfulness components of MBRP will be dismantled from the relapse prevention components by comparing the effects of an MBRP intervention to a relapse prevention (RP) intervention, thereby isolating the mindfulness effects. In the second aim, the proposed research will examine the mechanisms that may mediate the effects of MBRP by testing the effects of the intervention on inflammatory biomarkers (IL-6, IL-8, and TNFα) as well as the effect of MBRP on epigenetic regulation of key genes (DRD2, SLC6A3, DBH). Further, the proposed work will examine the effects of the intervention on the neural function of the reward system as well as connectivity in executive control networks in the brain. In Aim 3, the research will determine whether the effects of MBRP on immune system function and epigenetic regulation mediate the effects of MBRP on treatment outcomes. To that end, 226 patients will be randomized to 8 weeks of treatment with MBRP or RP. Putative mediators will be assayed at 4 and 8 weeks. Drinking outcomes will be assessed at 4, 8, 20 (12 weeks after the end of treatment), and 32 weeks (24 weeks after the end of treatment). The successful completion of the proposed research is expected to have significant clinical and scientific implications.