RC2 Alcohol-induced human striatal dopamine release related to alcoholism vulnera

RC2 酒精诱导的人纹状体多巴胺释放与酒精中毒伤病相关

• 批准号: 8128248
• 负责人: Anissa Abi-Dargham
• 金额: $ 25.46万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8128248
• 关键词: Address; Age; Age-Years; Agreement; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amphetamines; Animals; Behavior; Behavioral; Biological Markers; Biology; Body Water; Brain; Complement; Corpus striatum structure; Cues; Data; Data Set; Dependence; Development; Dopamine; Equilibrium; Ethnic Origin; Experimental Designs; Family; Functional disorder; Gender; Glutamates; Habits; Human; Juice; Lead; Learning; Measures; Mediating; Metabolism; Midbrain structure; Modeling; Molecular; Oral Administration; Partition Coefficient; Patients; Pharmaceutical Preparations; Population; Positron-Emission Tomography; Predisposing Factor; Prevention strategy; Process; Punishment; Raclopride; Recording of previous events; Relative (related person); Research; Resolution; Rewards; Risk; Risk Factors; Rodent; Sampling; Scanning; Smell Perception; Spatial Distribution; Staging; Stimulus; Taste Perception; Testing; Therapeutic; Ventral Striatum; addiction; alcohol behavior; alcohol exposure; alcohol response; base; cost; design; dopamine system; dopaminergic neuron; drinking; healthy volunteer; high risk; neuroimaging; preclinical study; problem drinker; radiotracer; receptor; receptor density; response; reward circuitry; socioeconomics; tool; translational neuroscience; transmission process; treatment strategy

CTNA3 will test the central hypothesis that the heritable risk for alcoholism reflects dysfunction of corticostriatal-midbrain circuitry, mediated by the interplay of glutamate and dopamine, that biases people to respond to drug-like rewards relative to delayed reward/punishments. This bias to respond to drug-like rewards leads to enhanced learning of alcohol-related associations, and facilitation of the development of habitual alcohol consumption. P2 will test this hypothesis by assessing alcohol induced dopamine (DA) release in the striatum in at risk subjects and in patients with alcoholism to demonstrate that risk is associated with an increased alcohol-induced DA release in the striatum while the transition from risk to habit is associated with a decreased response. Thus DA mediates the propensity to become addicted, and is altered by the process of addiction. SA #1. PET scanning will be performed with the D2/3 receptor radiotracer [[11]C]raclopride in 22 family history positive (FHP) healthy volunteers versus 22 FH negative (FHN) healthy volunteers. Groups will be matched on age, gender, ethnicity, socioeconomic background, and drinking habits. All subjects will be 21 to 25 years of age. [[11]C]raclopride scans will be obtained following the administration of oral alcohol at 0.75 g alcohol per kg body water or a sham drink on two separate days in counterbalanced order. The ventrostriatal [[11]C]raclopride specific to nonspecific equilibrium partition coefficient (BPND) will be measured and compared between the two groups. Alcohol-induced reduction in [[11]C]raclopride BP{ND} (ABP{ND}) will be compared between the two groups. SA#2. In the striatum, alcohol-induced DA intrasynaptic release is decreased in alcoholic subjects (n = 20) compared to matched healthy controls (n = 20). The same experimental design will be used as in SAI. Groups will be matched on age (25 to 45), gender, ethnicity, socioeconomic background, and drinking habits. Subjects will be nontreatment-seeking subjects with alcoholism. Alcohol-induced reduction in [[11]C]raclopride BP{ND} will be compared between the two groups. We will also test if baseline [[11]C]raclopride BP{ND} in FHP subjects (n = 22) is lower compared to FHN subjects (n = 22) (EA3) and explore if the propensity for Pavlovian Instrumental Transfer predicts the propensity to develop alcohol-related habit in all 44 subjects from SA1.

CTNA 3将测试中心假设，即酒精中毒的遗传风险反映了皮质纹状体-中脑回路的功能障碍，由谷氨酸和多巴胺的相互作用介导，使人们对药物样奖励的反应偏向于延迟奖励/惩罚。这种对药物样奖励的反应偏差导致了对酒精相关协会的学习增强，并促进了习惯性饮酒的发展。P2将通过评估风险受试者和酒精中毒患者纹状体中酒精诱导的多巴胺（DA）释放来验证这一假设，以证明风险与纹状体中酒精诱导的DA释放增加相关，而从风险到习惯的转变与反应降低相关。因此，DA介导成瘾倾向，并通过成瘾过程改变。SA #1。将在22名家族史阳性（FHP）健康志愿者和22名FH阴性（FHN）健康志愿者中使用D2/3受体放射性示踪剂[[11]C]雷氯必利进行PET扫描。各组将根据年龄、性别、种族、社会经济背景和饮酒习惯进行匹配。所有受试者的年龄均为21 - 25岁。[[11]C]雷氯必利扫描将在以0.75 g酒精/kg身体水的剂量口服酒精或以平衡顺序在不同的两天内饮用假饮料后获得。将测量腹侧纹状体[[11]C]雷氯必利特异性与非特异性平衡分配系数（BPND），并在两组之间进行比较。将比较两组间酒精诱导的[[11]C]雷氯必利BP{ND}（ABP{ND}）降低。SA #2。在纹状体， 与匹配的健康对照组（n = 20）相比，酒精受试者（n = 20）中酒精诱导的DA突触内释放减少。将使用与SAI相同的实验设计。各组将根据年龄（25至45岁）、性别、种族、社会经济背景和饮酒习惯进行匹配。受试者为非寻求治疗的酗酒受试者。将比较两组之间酒精诱导的[[11]C]雷氯必利BP{ND}降低。 我们还将检验FHP受试者（n = 22）的基线[[11]C]雷氯必利BP{ND}是否低于FHN受试者（n = 22）（EA 3），并探索巴甫洛夫仪器性转移的倾向是否预测了来自SA 1的所有44例受试者中形成酒精相关习惯的倾向。