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

测试 GABA 能/谷氨酸能药物对双相酗酒者自然奖励与酒精暗示的相对大脑激活的影响

基本信息

批准号：
9763315
负责人：
William Mellick
金额：
$ 6.06万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2020-07-31
项目状态：
已结题

项目摘要

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. !

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。与单独使用 AUD 或 BD 相比，这种方法与较差的临床结果相关。改进 AUD+BD 治疗的目的是确定针对共同神经生物学机制的新药物 AUD 和 BD 包括功能失调的大脑奖励电路研究表明，大脑奖励电路是相同的。 AUD 和 BD 个体都表现出对各种奖励（即食物、社交奖励和药物线索）的激活。奖励回路对不同类型的奖励“过敏”，但个体表现出哮喘。相对于其他奖励（例如金钱、食物和社交奖励[例如笑脸]）对酒精线索的激活而 BD 个体表现出对金钱和社会奖励的积极性增加，以 AUD+BD 表示。需要调查；然而，酒精的线索可能主要是由于“劫持”了大脑奖励通过长期接触乙醇而出现的系统电路；部分是通过谷氨酸和 y- 氨基丁酸（GABA）介导的内侧前额皮质-伏隔核（mPFC-）的神经可塑性 NAcc）途径动物研究表明该途径调节药物刺激的动机显着性和药物诱导的 mPFC-NAcc 功能连接的表达增加。与降低成瘾复发的可能性有关奖学金赞助者发表的研究结果。结果发现，包括 mPFC 在内的额叶内侧区域的谷氨酸和 GABA 水平异常低 AUD+BD；两者均与 AUD+BD 的药物治疗呈负相关。使用已知会改变谷氨酸（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暗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）。拟议的功能磁共振成像研究采用了一种新颖的自然奖励任务作为附加任务。一项正在进行的为期 3 周的加巴喷丁和 NAC 在 AUD+BD 中的双盲、交叉概念验证研究。检查加巴喷丁和/或 NAC 是否会改变相对于酒精与自然奖励的大脑激活目标 2 检查药物引起的 mPFC 中任务依赖性功能连接的变化。 NAcc 途径预计会：1) 显着降低大脑对酒精信号的激活。并增加对自然奖励的激活，2）显着降低 mPFC-NAcc 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拟议的 F32 研究是。第一个联合测量药物治疗干预对酒精暗示和自然刺激的大脑激活未来的成瘾治疗结果研究可能会采用这些方法。试图证明药物提示激活的减少和自然奖励激活的增加。！

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Trust and general risk-taking in externalizing adolescent inpatients versus non-externalizing psychiatric controls.

外化青少年住院患者与非外化精神病对照的信任和一般风险承担。

DOI：
10.21307/sjcapp-2019-013
发表时间：
2019
期刊：
Scandinavian journal of child and adolescent psychiatry and psychology
影响因子：
1.9
作者：
Mellick,William;Sharp,Carla;Sumlin,Eric
通讯作者：
Sumlin,Eric

Interpersonal Trust and Suicide Ideation Among Adolescent Psychiatric Inpatients: An Indirect Effect via Perceived Burdensomeness.

DOI：
10.1111/sltb.12433
发表时间：
2019-03
期刊：
Suicide & life-threatening behavior
影响因子：
3.2
作者：
Hill RM;Penner F;Vanwoerden S;Mellick W;Kazimi I;Sharp C
通讯作者：
Sharp C

Measurement invariance of depression symptom ratings across African American, Hispanic/Latino, and Caucasian adolescent psychiatric inpatients.

非裔美国人、西班牙裔/拉丁裔和白种人青少年精神病住院患者抑郁症状评级的测量不变性。

DOI：
10.1037/pas0000708
发表时间：
2019
期刊：
Psychological assessment
影响因子：
3.6
作者：
Mellick,William;Hatkevich,Claire;Venta,Amanda;Hill,RyanM;Kazimi,Iram;Elhai,JonD;Sharp,Carla
通讯作者：
Sharp,Carla

Depressive adolescent girls exhibit atypical social decision-making in an iterative trust game.

抑郁的青春期女孩在迭代的信任游戏中表现出非典型的社会决策。