Progesterone-Induced Gene Expression Changes and Risk of Relapse to Cocaine Use

黄体酮诱导的基因表达变化和可卡因吸毒复发的风险

基本信息

批准号：
7762313
负责人：
ROBERT DAVID BEECH
金额：
$ 24.83万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7762313
关键词：
Accounting Animal Model Animals Anxiety Behavioral Blood Blood Pressure Brain Candidate Disease Gene Clinical Clinical Trials Cocaine Cocaine Dependence Cues Data Development Distress Emotions Experimental Models Female Funding Future Gene Expression Genes Genomics Goals Gonadal Steroid Hormones Guided imagery Haplotypes Heart Rate Human Hydrocortisone Imagery Individual Individual Differences Investigation Laboratories Lymphocyte Measures Mediating Mediator of activation protein Molecular Monitor Neurons Pathway interactions Pattern Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Physiological Physiology Placebos Polymerase Chain Reaction Predisposition Progesterone Progesterone Receptors RNA Randomized Recruitment Activity Relapse Reverse Transcription Risk Salivary Sampling Second Messenger Systems Signal Pathway Stimulus Stress Study Subject Symptoms TNFRSF5 gene Time Transcript Variant Woman Women&apos s Health base cocaine use cost craving drug craving forest human female interest male men negative mood novel peripheral blood public health relevance response second messenger sex tool

项目摘要

DESCRIPTION (provided by applicant): This preliminary study, which will be of 2 years duration, will assess the relationship between changes in gene-expression induced by treatment with progesterone and laboratory measures of stress-induced craving, negative emotion, and physiology previously shown to predict risk for early relapse in cocaine addicted subjects. The long-term goal of this project is to develop novel molecular tools that can be used to predict and monitor the response to specific treatments for cocaine dependence. Preliminary studies have shown that men and women differ in their subjective and physiological responses to cocaine, as well as stress or drug-cue related stimuli associated with risk for relapse. Men and women also differ in their clinical response to various proposed pharmacological treatments for cocaine addiction. Differences in the level of gonadal steroids may underlie some or all of these differences. Recently, a number of small scale laboratory investigations and clinical trials have investigated progesterone as a possible treatment for cocaine addiction. Studies in animal models have shown that progesterone receptors are widely expressed in the brain and regulate the expression of a large number of genes in the brains of both female and male animals. In addition, progesterone has been shown to activate both the ERK/CREB/bcl-2 and Akt second messenger signaling pathways in neurons. These effects have been proposed to underlie the neuroprotective actions of progesterone in several experimental models. Activation of these pathways may oppose the actions of stress-induced patterns of gene expression, which could mediate increased risk for relapse in cocaine dependent individuals. In this study, we will recruit (n=60; 30 male and 30 female) treatment-seeking cocaine-dependent subjects who are currently being recruited to take part in a NIDA-funded study of progesterone effects on stress and cue- induced cocaine craving and relapse susceptibility. In that study, subjects are randomly assigned to receive either progesterone (400mg/day) or placebo for a period of five days and undergo brief guided imagery sessions involving personalized stressful, drug-cue or neutral-relaxing situations (one imagery condition per session). In the proposed study, we will isolate RNA from blood collected prior to treatment and on day 5 of treatment with either progesterone or placebo. Gene-expression levels will be assessed by microarray hybridization using Illumina Sentrix Beadchip (Human-6v2) arrays (the same platform used in our preliminary studies). Gene-expression levels will be correlated with drug craving, anxiety and emotion ratings, as well as behavioral distress responses, heart rate, blood pressure, and salivary cortisol measures assessed during each session. Differential expression of selected genes of interested will be confirmed using Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Specific aims include: (1) comparing progesterone-induced changes in peripheral blood gene-expression in cocaine-dependent men and women; and (2) identifying specific progesterone-regulated transcripts whose expression is correlated with the subjective response to stress or drug-cue related stimuli. PUBLIC HEALTH RELEVANCE: These studies will allow us to better understand the molecular basis for individual differences in the response to progesterone in cocaine dependent men and women. Better understanding of these differences will allow us to identify those individuals (both men and women) most likely to benefit from treatment with progesterone. In addition, better understanding of the mechanism of action of progesterone at the genomic level may help to guide the development of novel hormonally based pharmacotherapies for the treatment of cocaine dependence.

描述（由申请人提供）：这项为期 2 年的初步研究将评估黄体酮治疗引起的基因表达变化与先前显示的压力引起的渴望、负面情绪和生理学的实验室测量之间的关系预测可卡因成瘾受试者早期复发的风险。该项目的长期目标是开发新型分子工具，可用于预测和监测可卡因依赖特定治疗的反应。初步研究表明，男性和女性对可卡因的主观和生理反应以及与复发风险相关的压力或药物提示相关刺激存在差异。男性和女性对各种拟议的可卡因成瘾药物治疗的临床反应也不同。性腺类固醇水平的差异可能是部分或全部这些差异的基础。最近，一些小规模的实验室研究和临床试验已经研究了黄体酮作为可卡因成瘾的可能治疗方法。动物模型研究表明，孕激素受体在大脑中广泛表达，并调节雌性和雄性动物大脑中大量基因的表达。此外，黄体酮已被证明可以激活神经元中的 ERK/CREB/bcl-2 和 Akt 第二信使信号通路。在一些实验模型中，这些作用被认为是黄体酮神经保护作用的基础。这些途径的激活可能会对抗压力诱导的基因表达模式的作用，这可能会增加可卡因依赖者复发的风险。在这项研究中，我们将招募（n = 60；30 名男性和 30 名女性）寻求治疗的可卡因依赖受试者，他们目前正在招募参加 NIDA 资助的一项黄体酮对压力和提示诱导的可卡因渴望影响的研究和复发易感性。在该研究中，受试者被随机分配接受黄体酮（400 毫克/天）或安慰剂，为期五天，并接受简短的引导意象治疗，涉及个性化的压力、药物提示或中性放松情况（每次治疗一种意象条件）。在拟议的研究中，我们将从治疗前以及使用黄体酮或安慰剂治疗的第 5 天收集的血液中分离出 RNA。将使用 Illumina Sentrix Beadchip (Human-6v2) 阵列（与我们的初步研究中使用的平台相同）通过微阵列杂交来评估基因表达水平。基因表达水平将与药物渴望、焦虑和情绪评级以及每次治疗期间评估的行为困扰反应、心率、血压和唾液皮质醇测量值相关。将使用定量实时逆转录聚合酶链反应（qRT-PCR）来确认所选感兴趣基因的差异表达。具体目标包括：（1）比较黄体酮引起的可卡因依赖男性和女性外周血基因表达的变化； (2)鉴定特定的黄体酮调节转录物，其表达与对压力或药物提示相关刺激的主观反应相关。公共卫生相关性：这些研究将使我们能够更好地了解可卡因依赖男性和女性对黄体酮反应的个体差异的分子基础。更好地了解这些差异将使我们能够识别那些最有可能从黄体酮治疗中受益的个体（男性和女性）。此外，在基因组水平上更好地了解黄体酮的作用机制可能有助于指导开发用于治疗可卡因依赖的新型激素药物疗法。