Mechanisms of Adolescent Vulnerability to Drugs of Abuse

青少年时期是开始滥用药物的关键时期。那些开始吸毒的人 在青春期早期使用显示出更重的终身消费模式和更大的困难戒烟比那些 开始于年长的青少年或年轻人。流行病学研究表明， 从酒精和烟草到大麻和其他非法药物。这些发现导致了这样的假设， 酒精和烟草可以作为“入门”药物，使奖励途径对非法药物的作用敏感。我们 我建议在大鼠中进行综合行为和神经化学/神经解剖学研究，以评估这一点 假说.在具体目标1中，我们将使用静脉自我给药，以确定是否存在年龄和 可卡因和安非他明的奖励效应的性别差异。将对每种产品进行采集测试， 在青春期早期（出生后第28天（P））、青春期晚期（P38）和成年期（P90）使用药物。分开的 在动物组中，将检查急性和慢性给药对自发活动的影响 在每个年龄。这些动物的大脑将通过原位杂交进行处理，以分析药物- 诱导的神经元激活，通过即刻早期基因c-fos的mRNA表达来测量。在特定 目标2：我们将进行研究，评估尼古丁是否会增加青少年和/或成人的敏感性。 大脑对安非他明和可卡因的反应将进行自我给药研究，以确定 急性、非偶然的尼古丁治疗是否可以增加可卡因或安非他明的强化价值， 青少年或成年人。慢性、间歇性每日注射尼古丁对随后获得 还将审查可卡因和安非他明自我给药的情况。在平行研究中，慢性 还将在青少年中研究尼古丁对精神兴奋剂诱导的运动活动和神经元激活的影响 和成年人。虽然青春期是开始吸毒的主要时间段，但很少有研究评估 在这个发育时间点的药物作用机制。结合行为学和神经解剖学 我们建议的精神兴奋剂作用的研究应该提供对滥用行为的批判性理解。 药物对青少年大脑的影响，并澄清这些与成人大脑的不同或相似。

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.