Testing the Effect of GABAergic/glutamatergic Drugs on Relative Brain Activation to Natural Rewards versus Alcohol Cues in Bipolar Alcoholics

项目概要/摘要 酒精使用障碍（AUD）在双相情感障碍（BD）患者中非常普遍。共现AUD + BD 与单独的AUD或BD相比，与显著较差的临床结局相关。一种方法， 改善AUD + BD治疗的目的是确定靶向共同神经生物学机制的新型药物 包括奖励脑回路功能失调。研究表明，同样的电路 被激活以获得各种奖励（即，食物、社会奖励和药物线索）。AUD和BD个人都表现出 奖励电路"超敏反应"，尽管对不同类型的奖励。澳元个人表现出较高的 相对于其他奖励对酒精提示的激活（例如，金钱、食物和社会奖励[例如，Happy Faces]） 而BD个体对金钱和社会奖励的激活增加。以AUD + BD为单位的奖励 需要调查;然而，酒精线索可能主要是由于大脑奖励的“劫持”而突出的 系统电路，出现通过长期乙醇暴露;部分，通过谷氨酸和γ- 氨基丁酸（GABA）介导的内侧前额叶皮层-丘脑核（mPFC-1）的神经可塑性。 NAcc）途径。动物研究表明，这条通路调节药物刺激的动机显著性， 寻求毒品行为的表现。药物诱导的mPFC-NAcc功能连接增加 与降低成瘾复发的脆弱性有关。研究金赞助者发表的研究结果 结果显示，包括mPFC在内的内侧额叶区域的谷氨酸和GABA水平异常低， AUD + BD;两者均与酒精渴望呈负相关。AUD + BD的药物治疗 已知可改变谷氨酸（n-乙酰半胱氨酸; NAC）和GABA（加巴喷丁）水平的药物可能 通过减少对酒精提示的激活和增加对自然奖励的激活来调节奖励功能 (e.g.,食物和社会奖励）。拟议中的fMRI研究采用了一种新的自然奖励任务作为附加任务， 一项正在进行的加巴喷丁和NAC治疗AUD + BD的3周、双盲、交叉、概念验证研究。要求1 检查加巴喷丁和/或NAC是否改变相对于酒精的自然奖励的脑激活 线索目的2检查药物诱导的mPFC中任务依赖性功能连接的变化， NAcc途径。加巴喷丁和NAC预期：1）显著降低大脑对酒精提示的激活 增加对自然奖励的激活，以及2）显著降低mPFC-NAcc的功能连接， 酒精暗示，同时增加自然奖励的功能连接。探索性目标包括检查 Aim 1激活与酒精渴望和饮酒严重程度之间的关联。建议的F32研究是 第一个联合测量药物干预大脑激活酒精线索和自然 以AUD和/或BD表示的奖励。这些方法可能被未来的成瘾治疗结果研究所采用 试图证明药物线索激活的减少和自然奖励激活的增加。 !

PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) is highly prevalent in individuals with bipolar disorder (BD). Co-occurring AUD+BD is associated with significantly poorer clinical outcomes than AUD or BD alone. One approach towards improving AUD+BD treatment is to identify novel medications that target shared neurobiological mechanisms of AUD and BD including dysfunctional reward brain circuitry. Research shows the same circuitry to be activated to various rewards (i.e., food, social reward, and drug cues). AUD and BD individuals both exhibit reward circuitry “hypersensitivity” albeit to different types of rewards. AUD individuals show heightened activation to alcohol cues relative to other rewards (e.g., monetary, food, and social reward [e.g., happy faces]) whereas BD individuals show increased activation to monetary and social reward. Reward in AUD+BD is in need of investigation; however, alcohol cues may be principally salient due to the “hijacking” of brain reward system circuitry that emerges through prolonged ethanol exposure; in part, through glutamate and y- aminobutyric acid (GABA) mediated neuroplasticity of the medial prefrontal cortex-nucleus accumbens (mPFC- NAcc) pathway. Animal studies show this pathway modulates the motivational salience of drug stimuli and the expression of drug-seeking behaviors. Medication-induced increase in mPFC-NAcc functional connectivity has been associated with reduced vulnerability to addiction relapse. Published findings by the fellowship sponsor revealed abnormally low glutamate and GABA levels in a medial frontal region including the mPFC in AUD+BD; both were negatively associated with alcohol craving. Pharmacotherapuetic treatment of AUD+BD with medications known to alter levels of glutamate (n-acetylcysteine; NAC) and GABA (gabapentin) may modulate reward function by decreasing activation to alcohol cues and increasing activation to natural rewards (e.g., food and social reward). The proposed fMRI study employs a novel natural rewards task as an add-on to an ongoing 3-week, double-blind, crossover, proof-of-concept study of gabapentin and NAC in AUD+BD. Aim 1 examines whether gabapentin and/or NAC alter relative brain activation to natural rewards versus alcohol cues. Aim 2 examines medication-induced change in task-dependent functional connectivity in the mPFC- NAcc pathway. Gabapentin and NAC are expected to: 1) significantly decrease brain activation to alcohol cues and increase activation to natural rewards, and 2) significantly decrease mPFC-NAcc functional connectivity for alcohol cues while increasing functional connectivity for natural rewards. Exploratory aims include examining associations between Aim 1 activation and alcohol craving and drinking severity. The proposed F32 study is the first to jointly measure pharmacotherapeutic intervention on brain activation to alcohol cues and natural rewards in AUD and/or BD. These methods may be adopted by future addiction treatment outcomes studies attempting to evidence reduction in drug-cue activation and increased activation to natural rewards. !