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

描述（由申请人提供）：本研究的目的是确定青少年多巴胺能系统的发育是否是青少年易受酒精滥用并最终发展为酒精成瘾和依赖的重要因素。12岁至22岁是滥用包括酒精在内的各种物质的高危期，15岁至19岁左右是高峰期。从童年晚期到成年早期，在行为特征发生独特发育变化的同时，包括多巴胺能系统在内的神经递质系统也在发生变化。青春期多巴胺能系统的这些变化会影响行为，可能是青少年与成年人对酒精反应不同的潜在原因之一。利用FOS蛋白的免疫细胞化学染色，我们先前鉴定了暴露于乙醇（EtOH）激活的单个脑核，所有这些核要么含有多巴胺能神经元，要么支配其他核中的多巴胺能神经元。EtOH激活这些脑核会引起广泛的行为效应，包括奖励和依赖。动物研究表明，反复暴露于EtOH会导致EtOH诱导的行为敏感化（BS）的发展，其特征是运动活动增加和EtOH的自我管理，这两者都被证明与大脑各区域（包括前额叶皮层和纹状体）的多巴胺传递相关。药物诱导的人类BS被认为是成瘾和依赖的可能机制之一。综上所述，这些发现使我们假设，在青少年中发生的EtOH的不同行为影响是大脑中多巴胺能系统年龄依赖性发育变化的结果。为了验证这一假设，我们建议使用大鼠模型来实现以下目的：1)研究EtOH对大脑突触前多巴胺能神经元多巴胺释放的年龄依赖性影响；2)研究EtOH对大脑多巴胺摄取和再摄取的年龄依赖性影响；3)确定EtOH对多巴胺能系统的年龄依赖性是否会导致不同的行为效应。该项目将同时在分子、细胞和行为水平上定义年龄依赖性的etoh诱导的多巴胺能反应。拟议的研究将提供重要的信息，说明青少年对酒精滥用的脆弱性增加的可能机制。

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.