Alcohol's Effects on the Adolescent: Correlation Between the Dopaminergic System

酒精对青少年的影响：多巴胺能系统之间的相关性

• 批准号: 7944061
• 负责人: SULIE L. CHANG
• 金额: $ 51.73万
• 依托单位: SETON HALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944061
• 关键词: 19 year old; Adenylate Cyclase; Adolescence; Adolescent; Adult; Age; Age-Years; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Animals; Area; Behavior; Behavior Disorders; Behavioral; Brain; Cell Nucleus; Characteristics; Childhood; Chronic; Clinical Research; Corpus striatum structure; Coupled; DRD2 gene; Dependence; Development; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Drug usage; Ethanol; Exposure to; FOS Protein; Goals; Human; Individual; Lead; Mediating; Modeling; Molecular; Motor Activity; Neurotransmitters; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Play; Prefrontal Cortex; Rattus; Research; Reverse Transcriptase Polymerase Chain Reaction; Rewards; Role; Secretory Vesicles; Self Administration; Staining method; Stains; Study models; Synapses; Synaptic Cleft; System; Testing; Time; Western Blotting; addiction; age related; alcohol abuse therapy; alcohol behavior; alcohol effect; alcohol exposure; alcohol response; behavior influence; behavioral sensitization; clinically relevant; dopamine transporter; dopaminergic neuron; high risk; pre-clinical; public health relevance; receptor; response; transmission process; uptake; young adult

DESCRIPTION (provided by applicant): The objective of this research is to determine if the developing dopaminergic system in the adolescent is a significant factor in the adolescent's vulnerability to alcohol abuse and, ultimately, to developing alcohol addiction and dependence. The high risk period for abuse of various substances, including alcohol, is from 12 to 22 years of age, with a peak time from about 15 to 19 years old. From late childhood and into young adulthood, while unique developmental changes in behavioral characteristics are occurring, changes in neurotransmitter systems, including the dopaminergic system, are also taking place. These changes in the dopaminergic system during adolescence can influence behavior and could be one of the underlying causes of the differential response to alcohol seen in juveniles compared to adults. Using immunocytochemical staining of FOS protein, we previously identified individual brain nuclei activated by exposure to ethanol (EtOH), all of which either contain dopaminergic neurons or innervate dopaminergic neurons in other nuclei. EtOH activation of these brain nuclei cause a wide spectrum of behavioral effects, including rewarding and dependence. Animal studies have shown that repetitive exposure to EtOH causes the development of EtOH- induced behavioral sensitization (BS), which is characterized by increased locomotor activity and self- administration of EtOH, both of which have been shown to correlate with dopamine transmission in various areas of the brain, including the prefrontal cortex and striatum. Drug-induced BS in humans has been proposed as one of the possible mechanisms underlying addiction and dependence. Taken together, these findings have led us to hypothesize that the differential behavioral effects of EtOH that occur in adolescents are the result of age-dependent developmental changes in the dopaminergic system in the brain. To test this hypothesis, we propose to use the rat model to achieve the following aims: 1) To investigate the age-dependent effects of EtOH on dopamine release from pre-synaptic dopaminergic neurons in the brain; 2) To investigate the age-dependent effects of EtOH on dopamine uptake and re-uptake in the brain; and 3) To determine if the age-dependent effects of EtOH on the dopaminergic system result in differential behavioral effects. This project will define the age-dependent EtOH-induced dopaminergic responses at the molecular, cellular, and behavioral levels simultaneously. The proposed studies will provide important information on the possible mechanisms underlying the increased vulnerability to alcohol abuse in the adolescent. PUBLIC HEALTH RELEVANCE: The goal of this proposed research is to investigate, at both the molecular and behavioral levels, the increased vulnerability of adolescents to alcohol abuse that appears to result from age-dependent developmental changes in the dopaminergic system in the brain. We propose to use a rat model for these studies and to correlate alcohol-induced behavioral sensitization with alcohol's effects on various components of the dopaminergic system. Thus, the studies as proposed have high clinical relevance and will contribute significantly to the understanding and treatment of alcohol abuse and alcohol related behavior disorders in the adolescent.

描述（由申请人提供）：这项研究的目的是确定青少年中发展的多巴胺能系统是否是青少年易受酒精滥用的重要因素，最终是发展酒精成瘾和依赖性的重要因素。滥用包括酒精在内的各种物质的高风险期是12至22岁，高峰时间为15至19岁。从童年后期到成年，尽管行为特征的独特发展发生了变化，但神经递质系统的变化（包括多巴胺能系统）也发生了。青春期多巴胺能系统中的这些变化可能会影响行为，并且可能是与成年人相比，少年在少年中对酒精差异反应的基本原因之一。使用FOS蛋白的免疫细胞化学染色，我们先前通过暴露于乙醇（ETOH）激活的个体脑核，所有这些脑核都包含其他核中的多巴胺能神经元或神经多巴胺能神经元。这些脑核的EtOH激活会引起广泛的行为效应，包括奖励和依赖性。动物研究表明，重复接触ETOH会导致依托诱导的行为敏化（BS）的发展，其特征在于运动活性增加和ETOH的自我给药，这两种都已证明与大脑的各个区域（包括前额叶皮质和纹状体和纹状体）中的多巴胺传播相关。已经提出了药物诱导的BS作为成瘾和依赖性的可能机制之一。综上所述，这些发现使我们假设在青少年中发生的ETOH的差异行为效应是大脑多巴胺能系统的年龄依赖性发育变化的结果。为了检验这一假设，我们建议使用大鼠模型实现以下目的：1）研究EtOH对大脑中突触前多巴胺能神经元释放多巴胺释放的年龄依赖性作用； 2）研究ETOH对多巴胺摄取和重新摄取大脑的依赖性影响； 3）确定ETOH对多巴胺能系统的年龄依赖性影响是否会导致不同的行为效应。该项目将同时定义分子，细胞和行为水平的年龄依赖性ETOH诱导的多巴胺能反应。拟议的研究将提供有关青少年对酗酒脆弱性增加的可能机制的重要信息。 公共卫生相关性：这项拟议的研究的目的是在分子和行为水平上调查青少年对酒精滥用的脆弱性的增加，这似乎是由于大脑中多巴胺能系统的年龄依赖性发育变化而导致的。我们建议将大鼠模型用于这些研究，并将酒精诱导的行为敏化与酒精对多巴胺能系统各种成分的影响相关联。因此，所提出的研究具有很高的临床相关性，并将为青少年中酒精滥用和酒精相关的行为障碍的理解和治疗做出重大贡献。