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

描述(由申请人提供)：这项研究的目的是确定青少年体内发育中的多巴胺系统是否是青少年容易酗酒并最终形成酒精成瘾和依赖的一个重要因素。包括酒精在内的各种物质滥用的高危时期是12至22岁，高峰期约为15至19岁。从童年后期到成年后，虽然行为特征发生了独特的发育变化，但神经递质系统，包括多巴胺能系统，也发生了变化。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的不同反应的潜在原因之一。通过Fos蛋白的免疫细胞化学染色，我们以前发现了乙醇激活的单个脑核，这些核团中要么含有多巴胺能神经元，要么支配其他核团中的多巴胺能神经元。这些大脑核团的乙醇激活会引起广泛的行为影响，包括奖赏和依赖。动物研究表明，反复接触乙醇会导致乙醇诱导的行为敏化(BS)，其特征是运动活动增加和乙醇自我给药，这两者都被证明与大脑不同区域的多巴胺传递有关，包括前额叶和纹状体。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，这些发现让我们假设，在青少年中出现的乙醇的不同行为影响是大脑中多巴胺能系统随年龄增长而发生发育变化的结果。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)研究乙醇对脑内突触前多巴胺能神经元释放多巴胺的年龄依赖性影响；2)研究乙醇对脑内多巴胺摄取和再摄取的年龄依赖性影响；3)确定乙醇对多巴胺能系统的年龄依赖性影响是否导致不同的行为效应。这个项目将同时在分子、细胞和行为水平上定义依赖于年龄的乙醇诱导的多巴胺能反应。拟议的研究将提供关于青少年酗酒易感性增加的可能机制的重要信息。 公共卫生相关性：这项拟议研究的目标是在分子和行为水平上调查青少年对酒精滥用的易感性增加，这似乎是由于大脑中多巴胺能系统的年龄相关性发育变化造成的。我们建议使用大鼠模型进行这些研究，并将酒精诱导的行为敏感化与酒精对多巴胺能系统的各种成分的影响联系起来。因此，所提出的研究具有很高的临床相关性，并将对了解和治疗青少年的酒精滥用和酒精相关行为障碍做出重大贡献。

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.