Mechanisms of Adolescent Vulnerability to Drugs of Abuse

青少年容易滥用药物的机制

• 批准号: 7460735
• 负责人: FRANCES M. LESLIE
• 金额: $ 27.83万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460735
• 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; mRNA Expression; mature animal; neurochemistry; postnatal; psychostimulant; response; young adult

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.

描述（由申请人提供）：青春期是容易发生药物滥用的关键时期。 那些在青春期早期开始吸毒的人比那些在年龄较大的青少年或年轻人开始吸毒的人表现出终生吸毒量更大且戒烟难度更大的模式。 流行病学研究表明，吸毒的过程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：酒精和烟草可能作为“门户”药物，使奖励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假设。 在具体目标1中，我们将通过静脉自我给药来确定可卡因和安非他明的奖赏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）、青春期后期（P38）和成年期（P90）对每种药物进行获得测试。 在不同的动物组中，在每个年龄检查急性和慢性给药对运动活动的影响。 然后，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，通过立即早期基因 c-fos 的 mRNA 表达来测量。 在具体目标 2 中，我们将进行研究来评估尼古丁是否会增加青少年和/或成人大脑对安非他明和可卡因作用的敏感性。 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可以增加可卡因或安非他明对青少年或成人的增强作用。 还将研究长期、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，还将在青少年和成人中研究慢性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。 尽管青春期是开始使用药物的主要时间范围，但很少有研究评估该发育时间点的药物作用机制。 我们提出的精神刺激作用的行为和神经解剖学综合研究应该提供对滥用药物对青少年大脑的作用的批判性理解，并澄清这些作用与成人大脑的作用是否不同或相似。

项目成果

Locomotor and stress responses to nicotine differ in adolescent and adult rats.

• DOI: 10.1016/j.pbb.2010.04.010
• 发表时间: 2010-07
• 期刊: PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
• 影响因子: 3.6
• 作者: Cao, Junran;Belluzzi, James D.;Loughlin, Sandra E.;Dao, Jasmin M.;Chen, YiLing;Leslie, Frances M.
• 通讯作者: Leslie, Frances M.

Age-dependent effects of low-dose nicotine treatment on cocaine-induced behavioral plasticity in rats.

低剂量尼古丁治疗对可卡因诱导的大鼠行为可塑性的年龄依赖性影响。

• DOI: 10.1007/s00213-009-1642-0
• 发表时间: 2009
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: McQuown,SusanC;Dao,JasminM;Belluzzi,JamesD;Leslie,FrancesM
• 通讯作者: Leslie,FrancesM

The monoamine oxidase (MAO) inhibitor tranylcypromine enhances nicotine self-administration in rats through a mechanism independent of MAO inhibition.

• DOI: 10.1016/j.neuropharm.2011.03.007
• 发表时间: 2011-07
• 期刊: NEUROPHARMACOLOGY
• 影响因子: 4.7
• 作者: Lotfipour, Shahrdad;Arnold, Monica M.;Hogenkamp, Derk J.;Gee, Kelvin W.;Belluzzi, James D.;Leslie, Frances M.
• 通讯作者: Leslie, Frances M.

Age influences the effects of nicotine and monoamine oxidase inhibition on mood-related behaviors in rats.

• DOI: 10.1007/s00213-009-1760-8
• 发表时间: 2010-03
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Villegier, Anne-Sophie;Gallager, Brittney;Heston, Jon;Belluzzi, James D.;Leslie, Frances M.
• 通讯作者: Leslie, Frances M.

Serotonergic mechanism underlying tranylcypromine enhancement of nicotine self-administration.

反苯环丙明增强尼古丁自我给药的血清素机制。

• DOI: 10.1002/syn.20864
• 发表时间: 2011
• 期刊: Synapse (New York, N.Y.)
• 作者: Villégier,Anne-Sophie;Belluzzi,JamesD;Leslie,FrancesM
• 通讯作者: Leslie,FrancesM