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.

CTNA3将测试这一中心假设，即酒精中毒的可遗传风险反映了谷氨酸和多巴胺相互作用所介导的皮质纹状体-中脑回路功能障碍，这种功能使人们对药物样的奖励做出反应，而不是延迟的奖励/惩罚。这种偏向于对类似药物的奖励做出反应，导致对与酒精相关的协会的学习得到加强，并促进了习惯性饮酒的发展。P2将通过评估高危受试者和酒精中毒患者纹状体中酒精诱导的多巴胺(DA)释放来检验这一假设，以证明风险与酒精诱导的纹状体DA释放增加有关，而从风险到习惯的转变与反应减少有关。因此，DA调节成瘾的倾向，并被成瘾的过程改变。22名家族史阳性(FHP)健康志愿者和22名FH阴性(FHN)健康志愿者将用D2/3受体放射性示踪剂[[11]C]雷氯普利进行PET扫描。这些群体将在年龄、性别、种族、社会经济背景和饮酒习惯方面进行匹配。所有受试者的年龄在21岁到25岁之间。[[11]C]按平衡顺序连续两天口服每公斤水含0.75克酒精的口服酒精或假饮料后，可进行拉氯必利扫描。测量腹纹状体[[11]C]拉氯普利对非特异性平衡分配系数(BPND)的特异性，并在两组之间进行比较。比较两组间乙醇诱导的[[11]C]拉氯必利BP{ND}(ABP{ND})的降幅。SA#2.在纹状体中， 酒精受试者(n=20)与健康对照组(n=20)相比，酒精诱导的DA突触内释放量减少。将使用与SAI相同的实验设计。这些群体将在年龄(25至45岁)、性别、种族、社会经济背景和饮酒习惯方面进行匹配。受试者将是不寻求治疗的酗酒者。将比较两组间酒精诱导的[[11]C]拉氯必利BP{ND}的降低情况。 我们还将测试FHP受试者(n=22)的基线[[11]C]raclopide BP{ND}是否低于FHN受试者(n=22)(EA3)，并探索巴甫洛夫工具转移倾向是否预测SA1中所有44名受试者养成酒精相关习惯的倾向。