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. !

项目摘要/摘要酒精使用障碍（AUD）在双相情感障碍（BD）的个体中非常普遍。同时出现的aud+bd 与单独使用AUD或BD相比，与明显差的临床结果相关。一种方法改善AUD+BD处理是确定针对共有神经生物学机制的新型药物 AUD和BD，包括功能失调的奖励脑电路。研究表明相同的电路是激活各种奖励（即食品，社会奖励和毒品提示）。 AUD和BD个人都表现出来奖励电路“超敏反应”，尽管是不同类型的奖励。 aud个人显示出更高激活酒精提示相对于其他奖励（例如，货币，食物和社会奖励[例如，幸福的面孔]）而BD个人对货币和社会奖励的激活增加。 aud+bd中的奖励在需要投资；但是，由于大脑奖励的“劫持”，酒精提示可能主要是显着的通过长时间乙醇暴露出现的系统电路；部分通过谷氨酸和Y- 氨基丁酸（GABA）介导的中位前额叶皮质核核酸菌（MPFC-- NACC）途径。动物研究表明，该途径调节了药物刺激的动机显着性和寻求毒品行为的表达。药物诱导的MPFC-NACC功能连通性的增加具有与减少成瘾继电器的脆弱性有关。奖学金赞助商发表的发现在中间额叶区域（包括MPFC） aud+bd;两者都与渴望酒精相关。 AUD+BD的药物治疗已知可以改变谷氨酸水平（N-乙酰半胱氨酸； NAC）和GABA（GABAPENTIN）的药物可能通过减少对酒精提示的激活并增加激活自然奖励来调节奖励功能（例如，食品和社会奖励）。拟议的fMRI研究员工是一项新颖的自然奖励任务，作为一项持续的3周，双盲，跨界，概念验证研究的GABAPENTIN和NAC中的AUD+BD。目标1 检查加巴喷丁和/或NAC是否改变了对自然奖励与酒精的相对大脑的激活提示。 AIM 2考试药物诱导的MPFC-中任务依赖性功能连通性的变化变化 NACC途径。 Gabapentin和NAC预计：1）显着降低脑激活到酒精提示并增加对自然奖励的激活，以及2）显着降低MPFC-NACC功能连接性酒精提示同时提高自然奖励的功能连通性。探索目的包括检查 AIM 1激活与饮酒和饮酒严重程度之间的关联。拟议的F32研究是第一个共同测量有关大脑激活酒精提示和自然的药物治疗干预的一种奖励AUD和/或BD。这些方法可以通过未来的成瘾治疗结果研究来采用试图证明减少药物激活并增加自然奖励的激活。呢

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。