Brain and Behavioral Effects of PENK Gene Manipulation in Rat Nucleus Accumbens

PENK 基因操作对大鼠伏隔核的大脑和行为影响

• 批准号: 7485913
• 负责人: Hilarie C Tomasiewicz
• 金额: $ 4.34万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485913
• 关键词: 16 year old; Acute; Adolescence; Adolescent; Adult; Alcohol or Other Drugs use; Area; Behavior; Behavioral; Biology; Brain; Calculi; Cannabinoids; Cannabis; Cannabis sativa plant; Chronic; Data; Deltastab; Development; Disease; Dopamine; Down-Regulation; Drug Addiction; Drug abuse; Early Intervention; Emotions; Enkephalins; Epidemiologic Studies; Exposure to; Future; Gene Expression; Gene Transfer; Genes; Genetic; Goals; Heroin; Illicit Drugs; Intake; Knowledge; Laboratories; Learning; Link; Literature; Localized; Marijuana; Mediating; Mental disorders; Microdialysis; Molecular; Morphine; Motivation; Neurobiology; Neurotransmitters; Nucleus Accumbens; Opiates; Opioid; Opioid Peptide; Pharmaceutical Preparations; Predisposition; Prevention; Protein Overexpression; Public Health; RNA Interference; Rattus; Receptor Gene; Reporting; Rewards; Risk Factors; Self Administration; Societies; Structure; Substance Abuse, Other; Substance abuse problem; System; Teenagers; Testing; Tetrahydrocannabinol; Transfer RNA; Up-Regulation; Virus; Work; animal data; drug of abuse; early onset; endogenous cannabinoid system; endogenous opioids; genetic manipulation; hedonic; in vivo; insight; interest; neural circuit; neurochemistry; neurodevelopment; preproenkephalin; relating to nervous system; response; social; tool

DESCRIPTION (provided by applicant): Marijuana is the illicit drug most frequently used by teenagers, and exposure to cannabis normally predates the use of "heavy" drugs and psychiatric disorders. Such data appear to support the controversial "gateway" hypothesis of cannabis as a stepping stone towards abuse of other drugs. Despite strong epidemiological evidence of an association between cannabis use during adolescence and later drug abuse, few one-to-one neurobiological correlations between early cannabis use and subsequent drug abuse vulnerability exist. Reproducible animal data has shown that cannabis exposure during adolescence potentiated adult heroin self-administration behavior and caused discrete alterations of preproenkephalin (PENK), a gene important for reward and hedonic state, in the nucleus accumbens (Acb), a limbic-related brain area central to reward. The proposed work will directly test whether there is a causal link between PENK disturbance seen with early-onset cannabis use and progression to the use of other illicit drugs. Virus-mediated gene transfer (PENK overexpression) and RNA interference (PENK knockdown) will be used as genetic approaches to study the behavioral and neurochemical states associated with drug abuse. Specific Aim 1 will determine whether direct manipulation of the PENK gene in the Acb shell alters heroin self-administration behavior. Disturbances of neurotransmitters in brain areas linked to reward will be identified by studying whether genetic manipulation of PENK alters opiate-induced dopamine levels in the Acb shell using in vivo microdialysis (Specific Aim 2). To characterize specific molecular alterations that could underlie behavioral and neurochemical differences observed in association with genetic manipulation of PENK, brains will be analyzed for expression of genes and receptors linked to the opioid, DAergic, and cannabinoid neural systems (Specific Aim 3). Substance abuse is a major public health issue, and understanding risk factors predisposing to drug abuse disorders will be crucial to the prevention and treatment of these illnesses. Altogether, this project will provide insight as to whether there exists a long-term impact of cannabis exposure during development to substantiate a neurobiological "gateway" hypothesis and, if so, help to identify potential risk factors in adolescence that influence the vulnerability for drug abuse in adulthood.

描述（由申请人提供）：大麻是青少年最常使用的非法药物，接触大麻通常先于使用“重度”药物和精神疾病。这些数据似乎支持了大麻是滥用其他药物的垫脚石这一有争议的“门户”假说。尽管有强有力的流行病学证据表明，青少年时期使用大麻与后来滥用药物之间存在关联，但早期使用大麻与随后滥用药物的脆弱性之间几乎没有一对一的神经生物学相关性。可重复的动物数据表明，青少年时期的大麻暴露增强了成人海洛因自我给药行为，并导致伏隔核（Acb）中奖励和享乐状态重要基因前脑啡肽（PENK）的离散改变，伏隔核是与奖励有关的大脑边缘相关区域。拟议的工作将直接测试PENK紊乱与早期使用大麻和发展到使用其他非法药物之间是否存在因果关系。病毒介导的基因转移（PENK过表达）和RNA干扰（PENK敲低）将被用作研究与药物滥用相关的行为和神经化学状态的遗传方法。特异性目的1将确定是否直接操纵Acb壳中的PENK基因改变海洛因自我给药行为。通过体内微透析研究PENK的遗传操作是否会改变阿片类药物诱导的Acb壳中多巴胺水平，可以确定与奖励相关的大脑区域的神经递质紊乱（Specific Aim 2）。为了表征与PENK基因操作相关的行为和神经化学差异的特定分子改变，将分析大脑中与阿片、达能和大麻素神经系统相关的基因和受体的表达（specific Aim 3）。药物滥用是一个重大的公共卫生问题，了解导致药物滥用失调的风险因素对预防和治疗这些疾病至关重要。总而言之，该项目将深入了解在发育过程中接触大麻是否存在长期影响，以证实神经生物学的“门户”假说，如果是这样，将有助于确定青春期影响成年后药物滥用脆弱性的潜在风险因素。