Mechanisms of Adolescent Vulnerability to Drugs of Abuse

青少年容易滥用药物的机制

基本信息

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
项目类别：
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

项目摘要

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.

青春期是容易发生药物滥用的关键时期。那些开始吸毒的人与其他青少年相比，青春期早期的吸烟者终生消费量更大，戒烟难度更大。他们从年龄较大的青少年或年轻人开始。流行病学研究表明药物的进展从酒精和烟草到大麻和其他非法药物的使用。这些发现导致了这样的假设：酒精和烟草可以作为“门户”药物，使奖赏途径对非法药物的作用敏感。我们建议对大鼠进行综合行为和神经化学/神经解剖学研究来评估这一点假设。在具体目标1中，我们将使用静脉自我给药来确定是否存在年龄和年龄因素。可卡因和安非他明的奖赏效果存在性别差异。将为每个进行采集测试青春期早期（出生后（P）28）、青春期后期（P38）和成年期（P90）用药。在单独的动物组，将检查急性和慢性给药对运动活动的影响在每个年龄段。然后，这些动物的大脑将通过原位杂交进行处理，以进行药物分析。诱导神经元激活，通过立即早期基因 c-fos 的 mRNA 表达来测量。具体来说目标 2，我们将进行研究来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作用。将进行自我管理研究以确定急性、非偶然的尼古丁治疗是否可以增加可卡因或安非他明的增强价值青少年或成人。每天慢性、间歇性注射尼古丁对随后获得尼古丁的影响还将检查可卡因和安非他明的自我给药情况。在平行研究中，慢性病的影响尼古丁对精神兴奋剂引起的运动活动和神经元激活的影响也将在青少年中进行研究和成人。尽管青春期是开始吸毒的主要时间段，但很少有研究评估该发育时间点的药物作用机制。行为学和神经解剖学相结合我们建议的精神刺激行为研究应该为受虐待者的行为提供批判性的理解药物对青少年大脑的影响，并澄清这些药物与成人大脑是否不同或相似。