MODELS OF CNS SEROTONIN FUNCTIONING: ALCOHOL CONSUMPTION AND IMPAIRED IMPULSES

中枢神经系统血清素功能模型：饮酒和冲动受损

• 批准号: 6097588
• 负责人: James Dee Higley
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6097588
• 关键词: Macaca mulatta; aggression; alcoholic beverage consumption; animal breeding; behavioral /social science research tag; biological models; cerebrospinal fluid; ethology; hydroxyindoleacetate; maternal behavior; model design /development; neurotransmitter metabolism; nutrient intake activity; nutrition related tag; serotonin inhibitor; sleep

During the past year, our research included: (1) studies of genetic and environmental mechanisms that produce low cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations and alcohol consumption. Using pedigree analyses we were able to show for the first time that alcohol consumption is heritable in nonhuman primates, with fathers' and mothers' contributions accounting for about 30% of the variance in alcohol consumption. Early deleterious rearing environments and being solitary while drinking also increased the consumption of alcohol. In collaboration with Drs. K. Peter Lesch and Armin Heils at the University of Wuerzberg, Germany, we found evidence of an environment-dependent association between length variation in a variant of the 5-HT transporter gene region (5-HTTLPR, rh5-HTTLPR in rhesus) and CSF 5-HIAA concentrations in rhesus monkeys. Strain differences in both allele frequency and CSF 5-HIAA levels were also identified. Rhesus monkeys given the early deleterious experience of parental deprivation and then reared in absence of adults were differentiated by genotype in CSF 5-HIAA concentrations, whereas mother-reared monkeys were not differentiated. (2) the development of new technologies to study individual chronic alcohol consumption. This computerized methodology enabled us to identify individual monkeys living in large social groups, dispense alcohol to them, measure individual consumption patterns, thus allowing us to characterize large numbers of monkeys as high and low alcohol consumers. This methodology will allow us for the first time to study chronic alcohol consumption for 24-hours a day and enable other researchers interested in modeling alcohol consumption in primates to perform such studies using limited personnel resources. (3) pharmacological treatment studies of aggression, self-injurious behavior, and alcohol consumption. These studies showed that administration of tryptophan increased CNS serotonin functioning and eliminated self-injurious behavior. Treatments with the serotonin reuptake inhibitor sertraline reduced aggression and alcohol consumption in aggressive adult males. (4) studies investigating the role that the HPA system plays in alcohol consumption and its related behaviors. In one study we showed that high levels of plasma cortisol in infancy, obtained during a stressful experience, were predictive of high alcohol consumption three years later, when subjects were adolescents. Oral administration of a corticotrophin releasing hormone (CRH) antagonist reduced CSF CRH concentrations and plasma cortisol concentrations of as well as reducing their arousal. Studies in the next year will investigate its potential as a treatment for excessive alcohol consumption. (5) investigations of the role that taste plays in excessive consumption and whether an affinity for reinforcing agents such as sugar solutions are positively correlated with high alcohol consumption. In collaboration with Dr. Jim Woods at the University of Michigan studies showed that in high alcohol consuming monkeys, alcohol consumption remained high even when the alcohol solution was unsweetened, indicating that gustatory factors are not primary in producing high alcohol consumption; (6) comparisons of alcohol consumption between NIH rhesus monkeys and rhesus monkeys purchased at random: In this collaboration with Dr. Woods, we were able to show that NIH high alcohol consuming monkeys consume more alcohol than the typical monkeys picked at random, and that high alcohol consumption at the NIH in Poolesville predicts high consumption one year later in Michigan, using different methodologies. Furthermore, this preference for alcohol in NIH monkeys was evident over a wide variety of concentrations. The NIH high alcohol consuming monkeys also exhibited low CSF 5-HIAA concentrations, and independent of stock type, high consuming monkeys were more likely to exhibit low CSF 5-HIAA concentrations. Interestingly, high alcohol consumption was not correlated with high use of opiates or other reinforcing agents, indicating that preference for alcohol is not a generalized drug preference pattern and instead this preference is unique to alcohol. (7) a new program of study to investigate cognitive functioning and impulsivity in monkeys prone to high alcohol consumption and/or low CSF 5-HIAA concentrations. New methodologies were initiated to test monkey cognitive skills using a joystick and a computer. This methodology allows experimenters to vary experimental demands to test specific parameters of cognition in a primate. Low CSF 5-HIAA concentrations were associated with high impulsivity, as measured by approach and extension of limbs into of a novel opaque, black chamber with salient reinforcers located inside. Early deleterious rearing experiences produced subjects who were slow to attempt novel cognitive tasks. Dopamine and norepinephrine metabolite levels were associated with greater response to reward and higher arousal, respectively. (8) a collaboration was initiated with Drs. Salem and Hibbeln (LMBB) to investigate the role of essential fatty acids in CNS serotonin functioning. Infants fed a diet high in essential fatty acids were shown to be advanced in development and exhibited less fear-related behavior. As a corollary of this investigation, a laboratory-wide assessment of cholesterol and essential fatty acids were made in about 100 subjects to correlate with CSF 5-HIAA concentrations and violent behavior. Initial findings indicate that high CNS testosterone and low glucose were correlated with high rates of aggression in adolescent monkeys. Assays are underway to complete these analyses.

在过去的一年中，我们的研究包括：（1） 研究产生低遗传和环境机制 5-羟基丁乙酸的脑脊液浓度 （CSF 5-HIAA）浓度和饮酒。使用 血统分析我们能够首次表明 在非人类灵长类动物中，饮酒是可遗传的， 父亲和母亲的贡献约占30％ 饮酒的差异。早期有害的饲养 环境和孤独的同时饮酒也增加了 饮酒的消费。与Drs合作。 K. Peter Lesch 和德国武兹伯格大学的Armin Heils，我们 找到了与环境相关关联之间关联的证据 5-HT转运蛋白基因区域的变化长度变化 （5-HTTLPR，RH5-HTTLPR中的RH5-HTTLPR）和CSF 5-HIAA 恒河猴的浓度。等位基因的应变差异 还确定了频率和CSF 5-HIAA水平。恒河 猴子鉴于父母的早期有害经历 剥夺，然后在没有成年人的情况下饲养 通过CSF 5-HIAA浓度中的基因型，而 母亲饲养的猴子没有区别。 （2） 开发新技术以研究个人慢性 饮酒。这种计算机化方法使我们 确定生活在大型社会群体中的个别猴子，分配 酗酒，测量个人消费模式，从而 允许我们将大量猴子描述为高，并且 低酒精消费者。这种方法将使我们成为第一个 是时候每天学习24小时的长期饮酒了， 使其他有兴趣建模酒精的研究人员 灵长类动物的消费使用有限 人事资源。 （3） 侵略性，自我伤害行为和饮酒。这些 研究表明，色氨酸的给药增加了CNS 5-羟色胺发挥作用并消除了自我伤害行为。 5-羟色胺再摄取抑制剂舍曲林的治疗降低 侵略性成年男性的侵略性和饮酒。 （4） 研究调查HPA系统在酒精中起作用的作用 消费及其相关行为。在一项研究中，我们表明 在婴儿期间获得的高水平血浆皮质醇，在压力期间获得 经验，可以预测高饮用量三年 后来，当受试者是青少年时。口服 皮质营养素释放激素（CRH）拮抗剂减少了CSF CRH浓度和血浆皮质醇浓度的浓度 减少了他们的唤醒。明年的研究将调查其 潜力作为过度饮酒的治疗方法。 （5） 调查味道在过度消费中扮演的角色 以及对加固剂（例如糖）的亲和力是否亲和力 解决方案与高酒精消耗呈正相关。 与密歇根大学的吉姆·伍兹博士合作 研究表明，在饮酒量高的猴子中 即使酒精解决方案是 不加糖，表明味道不是主要的 产生高饮酒； （6）酒精的比较 NIH恒河猴和恒河猴之间的消费 随机购买：在与伍兹博士的合作中，我们 能够证明NIH高酒精消费猴子 比随机挑选的典型猴子食用更多的酒精 以及在Poolesville的NIH的大量饮酒 一年后在密歇根州预测高消费 不同的方法。此外，这种对酒精的偏爱 NIH猴子在各种浓度中都显而易见。 NIH高酒精消费猴子也表现出低CSF 5-HIAA浓度，独立于股票类型，高 消费猴子更有可能表现出低CSF 5-HIAA 浓度。有趣的是，大量饮酒不是 与大量使用鸦片或其他加固剂有关， 表明对酒精的偏爱不是普遍的药物 偏好模式，而这种偏好是酒精独有的。 （7）一项新的研究计划，以研究认知功能和 猴子的冲动性易于饮酒和/或 CSF 5-HIAA浓度低。新方法是 启动使用操纵杆和一个测试猴子认知技能 电脑。这种方法允许实验者改变 实验要求测试特定认知参数 灵长类动物。 CSF 5-HIAA浓度与 高冲动性，通过接近和四肢的扩展来衡量 进入一个新型不透明的黑色室，带有明显的增强剂 位于里面。早期有害的饲养经历产生了 尝试新颖的认知任务的受试者。多巴胺 去甲肾上腺素代谢物水平与更大的 对奖励和更高唤醒的反应。 （8）a 与Drs一起启动了合作。 Salem和Hibbeln（LMBB） 研究必需脂肪酸在中枢神经系统5-羟色胺中的作用 功能。婴儿喂养饮食高的婴儿是必需脂肪酸的饮食 证明在开发中是先进的，并且表现较少 与恐惧相关的行为。作为这项调查的推论， 实验室范围的胆固醇和必需脂肪酸评估 在大约100名受试者中与CSF 5-HIAA相关 集中和暴力行为。初始发现表明 高CNS睾丸激素和低葡萄糖与高葡萄糖相关 青少年猴子的侵略率。正在进行测定 完成这些分析。