Mechanisms of Adolescent Vulnerability to Drugs of Abuse

青少年容易滥用药物的机制

• 批准号: 7254794
• 负责人: FRANCES M. LESLIE
• 金额: $ 24.81万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254794
• 关键词: ARHGEF5 gene; Acute; Adolescence; Adolescent; Adult; Age; Alcohols; Amphetamines; Animals; Behavioral; Brain; CDC2L1 gene; Chronic; Cocaine; Condition; Consumption; Daily; Development; Dose; Drug effect disorder; Drug usage; Epidemiologic Studies; Evaluation; FOS gene; Gender; Illicit Drugs; Immediate-Early Genes; In Situ Hybridization; Injection of therapeutic agent; Intravenous; Label; Locomotion; MAPK14 gene; Marijuana; Measures; Messenger RNA; Monitor; Motor Activity; Neurons; Nicotine; Pathway interactions; Pattern; Pharmaceutical Preparations; Process; Rattus; Research; Research Personnel; Rewards; Saline; Self Administration; Sex Characteristics; Sprague-Dawley Rats; Substance abuse problem; Testing; Tobacco; aged; critical developmental period; day; drug mechanism; drug of abuse; drug testing; human PRIM2A protein; human TFRC protein; mRNA Expression; mature animal; neurochemistry; postnatal; psychostimulant; response; young adult

DESCRIPTION (provided by applicant): Adolescence is a critical period of vulnerability for the onset of substance abuse. Those who begin drug use in early adolescence show a pattern of heavier lifetime consumption and greater difficulty quitting than those who start as older adolescents or young adults. Epidemiological studies have characterized a progression of drug use from alcohol and tobacco to marijuana and other illicit drugs. Such findings have led to the hypothesis that alcohol and tobacco may serve as 'gateway' drugs that sensitize reward pathways to the action of illicit drugs. We propose to undertake integrative behavioral and neurochemical/neuroanatomical studies in rats to evaluate this hypothesis. In Specific Aim 1, we will use intravenous self-administration to determine whether there are age and sex differences in the rewarding effects of cocaine and amphetamine. Acquisition tests will be conducted for each drug during early adolescence (postnatal day (P) 28), late adolescence (P38) and adulthood (P90). In separate groups of animals, the effects of acute and chronic administration of drug on locomotor activity will be examined at each age. The brains of these animals will then be processed by in situ hybridization for analysis of drug-induced neuronal activation, as measured by expression of mRNA for the immediate early gene c-fos. In Specific Aim 2, we will conduct studies to evaluate whether nicotine increases the sensitivity of adolescent and/or adult brain to the actions of amphetamine and cocaine. Self-administration studies will be undertaken to determine whether acute, non-contingent nicotine treatment can increase the reinforcing value of cocaine or amphetamine in adolescents or adults. The effect of chronic, intermittent daily injection of nicotine on subsequent acquisition of cocaine and amphetamine self-administration will also be examined. In parallel studies, the effect of chronic nicotine on psychostimulant-induced locomotor activity and neuronal activation will also be studied in adolescents and adults. Although adolescence is the principal timeframe for initiation of drug use, few studies have evaluated mechanisms of drug action at this developmental timepoint. The combined behavioral and neuroanatomical studies of psychostimulant action that we propose should provide critical understanding of the actions of abused drugs on adolescent brain, and clarify whether these are different or similar to those in adult.

描述（由申请人提供）：青春期是滥用药物滥用的关键时期。 那些在青春期早期开始吸毒的人比那些从年龄较大的青少年或年轻人开始的终身消费量和戒烟更大的模式。 流行病学研究表明，从酒精和烟草到大麻和其他非法药物的药物使用的发展。 这样的发现导致了一个假设，即酒精和烟草可能是“门户”药物，可以使奖励途径对非法药物的作用敏感。 我们建议在大鼠中进行整合行为和神经化学/神经解剖学研究，以评估这一假设。 在特定的目标1中，我们将使用静脉自我给药来确定可卡因和苯丙胺的奖励作用中是否存在年龄和性别差异。 在青春期（产后（p）28），青春期（P38）和成年期（P90）中，将对每种药物进行采集测试。 在单独的动物组中，将在每个年龄段检查急性和长期给药对运动活性的影响。 然后，这些动物的大脑将通过原位杂交来处理，以分析药物诱导的神经元激活，如通过mRNA的表达来测量，即直接的早期基因C-FOS。 在特定目标2中，我们将进行研究，以评估尼古丁是否会增加青少年和/或成人大脑对苯丙胺和可卡因作用的敏感性。 将进行自我管理研究，以确定急性，非固定尼古丁治疗是否可以增加青少年或成人中可卡因或苯丙胺的增强价值。 还将检查慢性，间歇性每日注射尼古丁对随后获得可卡因和苯丙胺自我给药的影响。 在平行研究中，还将在青少年和成人中研究慢性尼古丁对精神刺激剂诱导的运动活性和神经元激活的影响。 尽管青春期是启动药物使用的主要时间范围，但很少有研究评估了该发育时点的药物作用机制。 我们提出的精神刺激作用的行为和神经解剖学研究应提供对滥用药物对青少年大脑的作用的批判性理解，并阐明它们与成年人的行为是否不同或相似。