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

描述（由申请方提供）：个体人类和动物对药物依赖的易感性差异很大。揭示这些差异的基质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制定更有效的预防和治疗策略。表观遗传过程可以通过允许基因组的微调来极大地增加基因组应答的复杂性。越来越多的证据表明，表观遗传过程有助于复杂的疾病，包括精神障碍。最近受到重视的表观遗传机制之一是RNA编辑。到目前为止，RNA编辑还没有被检查与药物成瘾倾向的关系;我们建议在本申请中这样做。5-羟色胺2C受体（5-HT 2CRs）的激活减弱，并且5-HT 2CRs的抑制增强多巴胺释放以及多种成瘾药物的药物寻求行为。5-HT 2CR的mRNA编辑可以产生多达24种不同的同种型，其功能活性各不相同。因此，我们提出作为本申请的总体假设，即个体的5-HT 2CR亚型库和/或受体的mRNA表达水平的变化可能是对滥用药物的反应性和成瘾倾向的表型差异的基础。已经确定，与低反应（LR）大鼠相比，对新环境具有高运动反应（高反应，HR）的大鼠表现出增强的药物相关行为。我们将采用表达这些表型的极端的动物，以便将腹侧被盖区（VTA）和前额叶皮层（RFC）中的5-HT 2CR mRNA编辑和表达与药物滥用的脆弱性联系起来。5-HT 2CR编辑将通过多个克隆的序列分析来确定，并且其mRNA表达将通过真实的时间PCR来测量。我们将检验以下假设：与LR相比，在HR的VTA和PFC中，5-HT 2CR mRNA编辑将增强，而其mRNA表达将降低。由于使用药物筛选动物的药物寻求行为差异可能会改变受体表达和/或编辑，因此采用HRs/LRs模型通过避免药物对研究结果的混淆效应带来了巨大的优势。

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.