Mechanisms of Adolescent Vulnerability to Drugs of Abuse

描述（由申请人提供）：青春期是药物滥用的关键时期。那些在青少年早期就开始吸毒的人比那些在青少年或青年时期开始吸毒的人表现出终生更重的消费模式和更大的戒烟困难。流行病学研究的特点是药物使用的进展，从酒精和烟草到大麻和其他非法药物。这些发现导致了一种假设，即酒精和烟草可能作为“入门”药物，使奖励途径对非法药物的作用敏感。我们建议在大鼠身上进行综合行为学和神经化学/神经解剖学研究来评估这一假设。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安非他明的奖励效果是否存在年龄和性别差异。将在青春期早期（出生后第28天）、青春期晚期（第38天）和成年期（第90天）对每种药物进行习得试验。在不同的动物组中，将在每个年龄检查急性和慢性给药对运动活动的影响。这些动物的大脑随后将通过原位杂交分析药物诱导的神经元激活，通过直接早期基因c-fos mRNA的表达来测量。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/或成人大脑对安非他明和可卡因的敏感性。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会增加青少年或成人对可卡因或安非他明的强化价值。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安非他明自我给药的影响。在平行研究中，慢性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也将在青少年和成人中进行研究。虽然青春期是开始使用药物的主要时间框架，但很少有研究评估药物在这个发育时间点的作用机制。我们提出的精神兴奋剂作用的行为学和神经解剖学的结合研究应该为滥用药物对青少年大脑的作用提供关键的理解，并澄清这些作用与成人的作用是不同的还是相似的。

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.