Neurobehavioral consequences of adolescent alcohol: Role of gonadal hormones

青少年酒精的神经行为后果：性腺激素的作用

• 批准号: 8079073
• 负责人: RATNA SIRCAR
• 金额: $ 22.97万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079073
• 关键词: Adolescence; Adolescent; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohols; American; Behavior; Behavioral; Biochemical; Brain; Complex; Development; Dose; Exhibits; Female; Female Adolescents; Goals; Gonadal Hormones; Hormonal; Impaired cognition; Impairment; Laboratories; Lead; Learning; Male Adolescents; Memory; Memory impairment; Molecular; N-Methyl-D-Aspartate Receptors; Nature; Neurosecretory Systems; Performance; Phase; Play; Prevention; Rattus; Reporting; Research; Rodent; Role; Sexual Maturation; Signaling Molecule; Substance of Abuse; Techniques; Teenagers; Testing; Time; adolescent alcohol; adolescent alcohol exposure; age related; alcohol behavior; alcohol consequences; alcohol effect; alcohol exposure; alcohol pharmacology; alcohol sensitivity; health economics; interdisciplinary approach; male; neurobehavioral; new therapeutic target; prepuberty; sex; social; underage drinking

DESCRIPTION (provided by applicant): Alcohol continues to be the number one substance of abuse among adolescents. Adolescence represents a critical window of vulnerability for initiating alcohol use, and in a large number of cases leading to increased alcohol intake. It is well documented that adolescents differ from adults in their sensitivity to alcohol. Our laboratory has reported that adolescent male rats, but not adult male rats, exposed to alcohol exhibit significant deficits in spatial learning and memory. The performance deficits persist for a significantly long period of time after the alcohol exposure is over. Alcohol in female adolescent rats also causes profound deficits in spatial learning and memory, but unlike adolescent male rats, their deficits do not persist beyond the alcohol exposure period. We have further shown that adolescent alcohol-induced behavioral deficits are associated with alterations in N-methyl-D-aspartate (NMDA) receptors in the brain. This proposal will explore the nature, mechanisms and consequences of alcohol exposure during adolescence on learning and memory in male and female rats, and the influence of pubertal gonadal hormones on alcohol behavior. We will test the overarching hypothesis that during adolescence pubertal gonadal hormones influence alcohol-induced behavioral deficit by modulating the NMDA receptor. The proposed rodent studies will (1) confirm and characterize the pharmacology of alcohol-induced memory deficit in adolescent rats, (2) examine the role of pubertal gonadal hormones in adolescent alcohol-induced memory deficit, (3) study modulation of NMDA receptor by pubertal gonadal hormones following adolescent alcohol exposure, (4) investigate signaling molecules that are affected by adolescent alcohol, (5) determine structural changes in the brains of adolescent alcohol exposed rats. These studies will employ a multidisciplinary approach comprising of biochemical, molecular, behavioral and anatomical techniques. Understanding age-related changes in the brain as it transitions from adolescence to adulthood, and the effects of pubertal gonadal hormones on alcohol-induced behavioral deficits will provide clues as to why the adolescent period is particularly vulnerable to use and abuse of alcohol, and lead to novel therapeutic targets that may be used for prevention and/or treatment of adolescent alcohol use and abuse.

描述（由申请人提供）：酒精仍然是青少年滥用的第一大物质。青春期是开始饮酒的关键时期，在很多情况下会导致酒精摄入量增加。有充分证据表明，青少年对酒精的敏感性与成年人不同。我们的实验室报告说，暴露于酒精的青春期雄性大鼠（但不是成年雄性大鼠）在空间学习和记忆方面表现出明显的缺陷。酒精暴露结束后，这种表现缺陷会持续相当长的一段时间。雌性青春期大鼠的酒精也会导致空间学习和记忆的严重缺陷，但与青春期雄性大鼠不同的是，它们的缺陷在酒精暴露期之后不会持续存在。我们进一步表明，青少年酒精引起的行为缺陷与大脑中 N-甲基-D-天冬氨酸 (NMDA) 受体的改变有关。该提案将探讨青春期酒精暴露对雄性和雌性大鼠学习和记忆的性质、机制和后果，以及青春期性腺激素对酒精行为的影响。我们将检验这一总体假设：青春期性腺激素通过调节 NMDA 受体来影响酒精引起的行为缺陷。拟议的啮齿动物研究将 (1) 确认和表征青春期大鼠酒精引起的记忆缺陷的药理学，(2) 检查青春期性腺激素在青少年酒精引起的记忆缺陷中的作用，(3) 研究 NMDA 受体的调节青少年酒精暴露后的青春期性腺激素，(4) 研究受青少年酒精影响的信号分子，(5) 确定青少年酒精暴露大鼠大脑的结构变化。这些研究将采用包括生化、分子、行为和解剖技术在内的多学科方法。了解从青春期过渡到成年时大脑中与年龄相关的变化，以及青春期性激素对酒精引起的行为缺陷的影响，将为解释为什么青春期特别容易使用和滥用酒精提供线索，并导致可用于预防和/或治疗青少年酒精使用和滥用的新治疗靶点。