Mechanisms of Adolescent Vulnerability to Drugs of Abuse

描述(由申请人提供)：青春期是药物滥用开始的关键时期。那些在青春期早期开始吸毒的人表现出一种模式，与那些从年长的青少年或年轻人开始吸毒的人相比，他们的终生吸毒量更大，戒烟难度更大。流行病学研究表明，毒品的使用经历了从酒精和烟草到大麻和其他非法药物的发展过程。这些发现导致了一种假设，即酒精和烟草可能是“门户”药物，使奖励途径对非法药物的行动变得敏感。我们建议在大鼠身上进行综合的行为学和神经化学/神经解剖学研究来评估这一假说。在具体目标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赏效应是否存在年龄和性别差异。每种药物的获取测试将在青春期早期(出生后28天)、青春期晚期(38天)和成年期(90天)进行。在不同的动物组中，将在每个年龄段检查急性和长期给药对运动活动的影响。然后，这些动物的大脑将被原位杂交处理，以分析药物诱导的神经元激活，这是通过即刻早期基因c-fos的mRNA表达来衡量的。在具体目标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行为的敏感性。将进行自我给药研究，以确定急性、非偶然尼古丁治疗是否可以增加可卡因或苯丙胺在青少年或成年人中的强化价值。此外，还将研究慢性间歇性每日注射尼古丁对随后的可卡因和苯丙胺自我给药的影响。在平行研究中，还将在青少年和成年人中研究慢性尼古丁对精神刺激剂诱导的运动活动和神经元激活的影响。虽然青春期是开始使用药物的主要时间框架，但很少有研究评估在这个发育时间点的药物作用机制。我们提出的精神刺激作用的联合行为和神经解剖学研究应该对滥用药物对青少年大脑的作用提供批判性的理解，并澄清这些行为是否与成人的不同或相似。

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.