Early Stress & Alcoholism: Neurobiological Analysis

描述（由申请人提供）：酗酒和酒精中毒是我们社会的主要负担。虽然过度饮酒模式的发展受到许多因素的影响，但一般的压力，特别是童年时期的压力，被认为是这一过程中的重要病因因素。事实上，慢性压力已被证明会改变许多与吸毒有关的大脑系统的神经传递，并改变各种滥用药物（包括酒精）的有益特性。然而，关于神经生物学对压力的反应如何改变受试者对酒精的反应，我们知之甚少。引人注目的是，大脑的许多区域，包括眼眶和内侧前额叶皮层、杏仁核和海马体，已经被证明可以调节对压力的反应，同时也是大脑奖励回路的一部分，而奖励回路在过度饮酒的发展中起着核心作用。神经回路的这种共性表明，这些区域可能在调节压力对饮酒的影响方面发挥作用。此外，中缝背核中含有5 -羟色胺的神经元，支配着上面列出的所有区域，以及下丘脑，是应激反应的关键调节剂，也能够改变对药物的反应。该项目于2003年首次获得资助，旨在继续研究童年压力和乙醇的相互作用，方法是采用一种经过充分研究的恒河猴的童年压力模型，即育儿。通过比较幼小的成年猕猴和来自同一群体的正常母猴，我们正在研究：1)饮酒行为，2)神经内分泌状况，3)血清素转运体和受体，以及促肾上腺皮质激素释放因子受体。与公共卫生的相关性：在童年经历过与父母分离等创伤性事件的成年人，酗酒和酗酒的风险更高。这种风险增加的原因尚不清楚。该研究旨在通过研究经历母亲分离的动物的饮酒行为和大脑结构和功能，直接解决童年压力导致成年酒精中毒的机制。这个项目提供的信息可以对如何保护受创伤的儿童免遭以后的药物滥用产生重要影响。

DESCRIPTION (provided by applicant): Alcohol abuse and alcoholism are major burdens for our society. While the development of excessive drinking patterns is influenced by many factors, stress in general, and stress during childhood in particular, are believed to be important etiological elements in this process. Indeed, chronic stress has been shown to alter neurotransmission in many brain systems linked to drug taking and alter the rewarding properties of a variety of abused drugs, including alcohol. Little is known, however about how the neurobiological response to stress might alter the way a subject responds to alcohol. Strikingly, many of the brain regions, including the orbital and medial prefrontal cortex, the amygdala and the hippocampus, that have been shown to modulate the response to stress, are also part of the brain reward circuitry, which is central in the development of excessive drinking. This commonality of neural circuitry suggests that these regions may play a role in mediating the effects of stress on alcohol consumption. In addition, serotonin-containing neurons of the dorsal raphe nucleus, which innervates all of the areas listed above, along with the hypothalamus, is a key modulator of the stress response, and is able to modify the response to drugs as well. This project, first funded in 2003, is designed to continue to study the interaction of childhood stress and ethanol by employing a well-studied model of childhood stress in rhesus monkeys, nursery-rearing. By comparing young adult nursery-reared monkeys to normal motherreared controls from the same colony, we are studying: 1) drinking behavior, 2) neuroendocrine status, 3) the serotonin transporter and receptors, and Corticotropin releasing factor receptors. Relevance to Public Health: Adults, who in childhood experience traumatic events like separation from their parents, are at increased risk for alcohol abuse and alcoholism. The causes for this increased risk are unknown. The proposed studies are designed to directly address the mechanisms by which childhood stress leads to adult alcoholism by studying the drinking behavior and brain structure and function of animals that experienced maternal separation. This information from this project can have important influences on how traumatized children may be protected from later substance abuse.