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

项目摘要/摘要 酒精使用障碍(AUD)在双相情感障碍(BD)患者中非常普遍。共同发生的AUD BD 与单纯的AUD或BD相比，临床结果明显更差。一种方法是 改进AUD BD治疗是为了确定针对共同神经生物学机制的新药物 AUD和BD包括功能失调的奖赏脑回路。研究表明，相同的电路是 对各种奖励(即食物、社会奖励和药物提示)的激活。澳大利亚和BD个人都展示了 奖赏回路“超敏感”，尽管对不同类型的奖赏。澳元个人表现出高度的 与其他奖励(例如，金钱、食物和社会奖励[例如，笑脸])相比，对酒精暗示的激活 而BD个体则表现出对金钱和社会回报的激活程度增加。澳元奖励BD到了 需要调查；然而，酒精提示可能主要是由于大脑奖励的“劫持”而引起的 通过长期接触酒精而出现的系统电路；部分通过谷氨酸和γ- 氨基丁酸(GABA)介导的内侧前额叶皮质-伏核(mPFC- NACC)途径。动物研究表明，这一途径调节药物刺激的动机突显和 毒品寻觅行为的表现。药物诱导的mPFC-NAcc功能连接增加 与降低成瘾复发的易感性有关。奖学金发起人发表的研究结果 在包括mPFC在内的额叶内侧区域显示异常低的谷氨酸和GABA水平 AUD和BD；两者都与饮酒欲望负相关。AUD BD的药物治疗 已知可以改变谷氨酸(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 (例如，食物和社会奖励)。拟议的功能磁共振研究采用了一种新的自然奖励任务作为附加任务 一项正在进行的为期3周的双盲交叉概念验证研究，加巴喷丁和NAC在澳大利亚BD中的应用。目标1 检查加巴喷丁和/或NAC是否会改变大脑对自然奖励和酒精的相对激活 暗示。目的2研究药物诱导的mPFC中任务依赖性功能连接的变化。 NACC途径。加巴喷丁和NAC有望：1)显著降低大脑对酒精信号的激活 并增加对自然奖励的激活，以及2)显著降低mPFC-NAcc功能连接 酒精提示，同时增加功能连接，以获得自然奖励。探索性目标包括检查 AIM 1激活与酒精渴求和饮酒严重程度之间的关系。建议的F32研究是 首次联合测量药物治疗干预对酒精刺激和自然刺激脑活动的影响 奖励以澳元和/或BD为单位。这些方法可能被未来的成瘾治疗结果研究所采用。 试图证明药物线索的激活减少，而对自然奖励的激活增加。 好了！

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. !