Mechanisms of Adolescent Vulnerability to Drugs of Abuse

青少年容易滥用药物的机制

• 批准号: 7490294
• 负责人: FRANCES M. LESLIE
• 金额: $ 3.68万
• 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/7490294
• 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; mature animal; neurochemistry; postnatal; psychostimulant; response; young adult

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 ofmRNA 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.

青春期是滥用药物滥用的关键时期。那些开始毒品的人 在青春期早期使用显示出比那些较重的终生消费和更大的戒烟模式 他们从年长的青少年或年轻人开始。流行病学研究表征了药物的进展 从酒精和烟草到大麻和其他非法药物的使用。这样的发现导致了以下假设 酒精和烟草可以用作“门户”药物，使奖励途径敏感非法药物的作用。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点 假设。在特定的目标1中，我们将使用静脉自我管理来确定是否有年龄和 可卡因和苯丙胺奖励作用的性别差异。将对每个 青春期初期（产后（P）28），青春期晚期（P38）和成年（P90）的药物。在单独 将检查动物组，急性和长期给药药物对运动活性的影响 在每个年龄。然后，这些动物的大脑将通过原位杂交来处理，以分析药物 通过MRNA的表达来测量诱导的神经元激活，用于立即的早期基因C-FOS。具体 AIM 2，我们将进行研究以评估尼古丁是否会增加青少年和/或成人的敏感性 大脑对苯丙胺和可卡因的作用。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可卡因或苯丙胺的增强价值 青少年或成年人。慢性，间歇性每日注射尼古丁的影响随后收购 还将检查可卡因和苯丙胺自我给药。在平行研究中，慢性的影响 尼古丁在精神刺激诱导的运动活性和神经元激活中也将在青少年中进行研究 和成人。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 在此发育时点，药物作用的机制。联合行为和神经解剖学 我们提出的心理刺激行动的研究应提供对虐待行为的批判性理解 青少年大脑上的药物，并阐明它们是否与成年人不同或相似。