Early stress & alcoholism: Neurobiological analysis

描述(申请人提供)：酗酒和酗酒是我们社会的主要负担。虽然酒精中毒的发展受到许多因素的影响，但应激被认为是一个重要的病因。事实上，慢性应激已被证明会改变许多大脑系统中的神经传递，并改变包括酒精在内的各种滥用药物的有益特性。此外，童年时期的压力会导致后来的一系列不良结果，包括抑郁、焦虑症和药物滥用。关于压力反应的神经生物学基础，以及这可能如何改变受试者对酒精的反应方式，人们知之甚少。引人注目的是，许多大脑区域，包括眼眶和内侧前额叶皮质、杏仁核和海马体，已经被证明可以调节对压力的反应，它们也是大脑奖励电路的一部分，后者改变了对药物的反应。神经回路的这种共性表明，这些区域可能在调节压力对酒精消费的影响方面发挥作用。此外，与下丘脑一起支配上述所有区域的5-羟色胺是应激反应中的关键神经递质，也在调整药物反应方面发挥作用。一种慢性压力模型是当幼猴在出生时与母亲分开并在托儿所饲养时产生的。苗圃饲养的猴子表现出一系列与正常猴子在认知、行为和生理上的不同，包括它们大脑5-羟色胺系统的失调，以及在接触酒精时过度饮酒的倾向。 因此，本项目的目标是：1)研究育苗和母养猕猴之间5-羟色胺转运体、5-羟色胺受体和5-羟色胺基因密度的差异；2)表征这两组猴子在固定剂量和即兴饮酒环境中的饮酒行为；以及研究固定剂量饮酒环境和即兴饮酒环境中5-羟色胺系统的变化。

DESCRIPTION (provided by applicant): Alcohol abuse and alcoholism are major burdens for our society. While the development of alcoholism is influenced by many factors, stress is believed to be one important etiological element. Indeed, chronic stress has been shown to alter neurotransmission in many brain systems and alter the rewarding properties of a variety of abused drugs, including alcohol. Moreover, stress during childhood contributes to an array of poor outcomes later in life including depression, anxiety disorders, and substance abuse. Little is known about the neurobiolgoical basis of the response to stress and how that 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 modifies the response to drugs. 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, which innervates all of the areas listed above, along with the hypothalamus, is a key neurotransmitter in the stress response, and plays a role in modifying the response to drugs as well. One model of chronic stress is produced when infant monkeys are separated from their mothers at birth and reared in a nursery. Nursery reared monkeys show an array of cognitive, behavioral, and physiological differences from normal monkeys, including dysregulation of their brain serotonin systems and a propensity to drink excessively when exposed to alcohol. Thus, the goals of this project are to: 1) study the differences in the densities of the serotonin transporter, serotonin receptors, and in serotonin gene between nursery-reared and mother-reared monkeys; 2) to characterize the drinking behaviors of these two groups of monkeys in fixed-dose and ad lib drinking environments; and to examine the changes in the serotonin system in fixed-dose vs. ad lib drinking environments.