Vulnerability to Addiction: A Role for 5-HT2C Receptor Editing and Expression

成瘾脆弱性：5-HT2C 受体编辑和表达的作用

• 批准号: 7291043
• 负责人: STELLA DRACHEVA
• 金额: $ 12.57万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7291043
• 关键词: Adenosine; Agonist; Alcohols; Amphetamines; Animal Model; Animals; Area; Attenuated; Behavior; Behavioral; Biology; Brain; Brain region; Cocaine; Complex; Development; Disease; Dopamine; Drug Addiction; Drug abuse; Drug usage; Environment; Environmental Exposure; Epigenetic Process; Exhibits; Future; G-Protein-Coupled Receptors; Gene Expression; Genome; Genomics; Harvest; Human; Individual; Individual Differences; Inosine; Laboratories; Lasers; Localized; Measures; Mediating; Mental disorders; Messenger RNA; Microdissection; Modeling; Motor Activity; Neurotransmitters; Nicotine; Nucleus Accumbens; Pharmaceutical Preparations; Phenotype; Polymerase Chain Reaction; Predisposition; Prefrontal Cortex; Preventive; Property; Protein Isoforms; RNA Editing; Rat Strains; Rattus; Role; Self Administration; Sequence Analysis; Serotonin; Serotonin Receptor 5-HT2C; Signal Pathway; Substantia nigra structure; System; Techniques; Testing; Time; Tissues; Variant; Ventral Tegmental Area; addiction; cost; dopaminergic neuron; drug of abuse; drug seeking behavior; insight; mRNA Expression; neurochemistry; novel; pars compacta; psychostimulant; receptor; receptor expression; response

DESCRIPTION (provided by applicant): Individual humans and animals vary widely in their susceptibility to drug dependence. Uncovering the substrates of these differences will provide important insights into the biology of drug addiction and will facilitate the development of more effective preventive and treatment strategies for this devastating illness. Epigenetic processes can greatly increase the complexity of genomic responses by allowing fine-tuning of the genome. Increasing evidence suggests that epigenetic processes contribute to complex diseases, including mental disorders. One of the recently appreciated epigenetic mechanisms is RNA editing. To date, RNA editing has not been examined in relation to the propensity for drug addiction; we propose to do so in the present application. Activation of the serotonin 2C receptors (5-HT2CRs) attenuates, and inhibition of 5-HT2CRs potentiates dopamine release as well as drug-seeking behavior of a variety of addictive drugs. The mRNA editing of the 5-HT2CR may give rise to up to 24 distinct isoforms which vary in their functional activity. We, therefore, propose as the overarching hypothesis of this application that that variations in an individual's repertoire of the 5-HT2CR isoforms and/or in the mRNA expression level of the receptor may underlie phenotypic differences in responsivity to drugs of abuse and predisposition to addiction. It has been established that rats with a high locomotor response to a novel environment (high responders, HRs) exhibit enhanced drug-related behaviors compared with rats with a low response (LRs). We will employ animals that express the extremes of these phenotypes in order to relate 5-HT2CR mRNA editing and expression in the ventral tegmental area (VTA) and prefrontal cortex (RFC) to vulnerability to drug abuse. The 5-HT2CR editing will be determined by sequence analysis of multiple clones, and its mRNA expression will be measured by real time PCR. We will test the hypotheses that 5-HT2CR mRNA editing will be enhanced, while its mRNA expression will be lower, in the VTA and PFC of HRs compared to LRs. Because the use of drugs to screen the animals for differences in drug-seeking behavior might alter receptor expression and/or editing, employing the HRs/LRs model brings about an enormous advantage by avoiding the confounding effects of drugs on the results of the study.

描述（由申请人提供）：个别人类和动物的敏感性差异很大。揭示这些差异的底物将为药物成瘾的生物学提供重要的见解，并将促进为这种毁灭性疾病的更有效的预防和治疗策略的发展。表观遗传过程可以通过允许对基因组进行微调来大大提高基因组反应的复杂性。越来越多的证据表明，表观遗传过程有助于复杂的疾病，包括精神疾病。最近所欣赏的表观遗传机制之一是RNA编辑。迄今为止，尚未针对吸毒倾向研究RNA编辑。我们建议在本申请中这样做。血清素2C受体（5-HT2CR）的激活减弱，并抑制5-HT2CRS增强多巴胺的释放以及多种成瘾药物的吸毒行为。 5-HT2CR的mRNA编辑可能会产生多达24种不同的同工型，它们的功能活性不同。因此，我们提出，作为该应用的总体假设，即个人对5-HT2CR同工型和/或受体mRNA表达水平的曲目的变化可能是对滥用药物和对成瘾症的滥用药物反应性的表型差异的基础。已经确定，与响应较低（LRS）相比，对新型环境（高反应者，HRS）具有高运动反应的大鼠表现出增强的与药物相关的行为。我们将采用表达这些表型极端的动物，以将5-HT2CR mRNA的编辑和表达联系起来，并在腹侧段区域（VTA）（VTA）和前额叶皮层（RFC）中与对药物滥用的脆弱性联系起来。 5-HT2CR编辑将通过多个克隆的序列分析确定，其mRNA表达将通过实时PCR测量。我们将测试与LRS相比，在HRS的VTA和PFC中，将增强5-HT2CR mRNA编辑，而其mRNA表达将较低。因为使用药物来筛查动物的寻求药物行为差异可能会改变受体表达和/或编辑，而采用HRS/LRS模型则通过避免药物对研究结果的混杂作用来带来巨大的优势。