Ontogeny of Drug Exposure and Mood Dysregulation.

描述（由申请人提供）：药物使用与抑郁和焦虑（即共发病）障碍的共存已经得到了很好的证实，了解这些神经精神疾病之间的复杂关系具有重要的治疗和预后意义。虽然大多数研究的重点是成年人口，但开始使用药物是在早年开始的，因为报告表明，青少年（即8 -12年级的儿童）终生吸毒的非法药物使用率为37%，香烟使用率为41%。青春期是大脑仍在经历发育变化的关键时期。由于早期生活经历可能导致神经可塑性调节对压力/药物的脆弱性，或对精神障碍的易感性，因此表征早期药物暴露的神经生物学后果以及它如何影响大脑通路以介导病理行为是很重要的。这些研究考察了雄性大鼠在青春期接触尼古丁的短期和长期神经生物学后果。本研究在发育中的啮齿动物模型中研究了大脑食欲神经回路在药物暴露的短期和长期行为和生化后果中的作用。这种方法是新颖的，因为它关注的是大脑的食欲区域（腹侧被盖区和伏隔核），这对动机、奖励和精神运动活动很重要，而且因为它关注的是一个发育时期，在这个时期开始吸毒/滥用和情绪紧张经常发生。目的1研究是否暴露于尼古丁在青春期影响情绪反应使用行为测试设计，以评估动物的情感状态。这些评估包括：(a)对引起情绪的刺激的行为反应（开放场地，高难度迷宫，强迫游泳压力，蔗糖偏好），(b)天然（蔗糖）和(c)药物奖励（尼古丁和可卡因）。目的2通过鉴定暴露于尼古丁调节的基因产物，利用基本蛋白质生物化学来评估该回路的生化完整性。目的3确定这些尼古丁调节蛋白的功能意义，使用病毒载体，评估它们如何影响青少年大脑，导致神经适应，可能增加成年后神经精神疾病的易感性。从这些研究中获得的数据将提高我们对青春期药物暴露在以后生活中调解病理行为中所起作用的理解。

DESCRIPTION (provided by applicant): The co-occurrence of drug use with depression and anxiety (i.e., co-morbidity) disorders is well established, and understanding the complex relationship between these neuropsychiatric disorders is of great therapeutic and prognostic importance. Although most research has focused on adult populations, the initiation into substance use starts during the early years, as reports indicate lifetime drug use rates in adolescents (i.e., children from 8th-12th grades) of 37% for illegal substances and 41% for cigarettes. Adolescence is a critical period during which the brain is still undergoing developmental changes. Because early-life experiences can result in neural plasticity regulating vulnerability to stress/drugs, or predisposition for mental disorders, it is important to characterize the neurobiological consequences of drug exposure during the early years, and how it influences brain pathways to mediate pathological behavior. These studies examine the short- and long-term neurobiological consequences of exposure to nicotine during adolescence in male rats. This proposal studies the role of brain's appetitive neural circuits in the short- and long-term behavioral and biochemical consequences of drug exposure within the proposed developmental rodent model. This approach is novel because it focuses on appetitive regions of the brain (the ventral tegmental area and the nucleus accumbens) important for motivation, reward, and psychomotor activity, and because it focuses on a developmental period where initiation to drug use/abuse and heightened emotional stress often occur. Aim 1 examines whether exposure to nicotine during adolescence influences emotional reactivity using behavioral tests designed to assess an animal's affective state. These include assessing: (a) behavioral reactivity to emotion-eliciting stimuli (open-field, elevated plus-maze, forced swim stress, sucrose preference), (b) natural (sucrose) and (c) drug reward (nicotine and cocaine). Aim 2 assesses the biochemical integrity of this circuit, using basic protein biochemistry, by identifying gene products regulated by exposure to nicotine. Aim 3 determines the functional significance of these nicotine-regulated proteins, using viral vectors, to assess how they influence adolescent brain, resulting in neural adaptations that may increase vulnerability to neuropsychiatric disorders later in adulthood. Data obtained from these studies will improve our understanding of the role drug exposure during adolescence plays in mediating pathological behavior later in life. PUBLIC HEALTH RELEVANCE: The co-occurrence of drug use/abuse with depression and anxiety disorders (i.e., comorbidity) is well established, and understanding the complex relationship between these neuropsychiatric disorders is of great therapeutic and prognostic importance. Because early-life experiences can result in neural plasticity regulating vulnerability to stress/drugs of abuse, and predisposition for mental disorders, it is important to characterize the neurobiological consequences of drug exposure during developmental periods prior to adulthood, and how drug insults influence brain pathways to mediate dysregulated behavior later in life.