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

• 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
• 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' 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

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）：这项初步研究将持续2年，将评估孕酮治疗诱导的基因表达变化与压力诱导的渴望、负面情绪和生理学实验室测量之间的关系，这些实验室测量先前显示可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的分子工具，可用于预测和监测对可卡因依赖特定治疗的反应。初步研究表明，男性和女性在对可卡因的主观和生理反应以及与复吸风险相关的压力或药物提示相关刺激方面存在差异。男性和女性对各种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孕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，孕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。这些作用已被认为是孕酮在几个实验模型中的神经保护作用的基础。这些途径的激活可能会对抗应激诱导的基因表达模式的作用，这可能会介导可卡因依赖者复发风险的增加。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由NIDA资助的孕酮对压力和线索诱导的可卡因渴望和复发易感性的影响的研究。在这项研究中，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，并接受简短的引导性意象会话，涉及个性化的压力，药物提示或中性放松情况（每次会话一个意象条件）。在拟议的研究中，我们将从治疗前和孕酮或安慰剂治疗第5天收集的血液中分离RNA。基因表达水平将通过使用Illumina Sentrix Beadchip（Human-6v 2）阵列（与我们的初步研究中使用的相同平台）的微阵列杂交来评估。基因表达水平将与药物渴望，焦虑和情绪评级，以及行为困扰反应，心率，血压和唾液皮质醇测量在每次会议期间进行评估。将使用定量实时逆转录聚合酶链反应（qRT-PCR）确认所选感兴趣基因的差异表达。具体目标包括：（1）比较可卡因依赖性男性和女性外周血基因表达中的孕酮诱导的变化;和（2）鉴定其表达与对压力或药物线索相关刺激的主观反应相关的特定孕酮调节的转录物。 公共卫生关系：这些研究将使我们更好地了解可卡因依赖男性和女性对孕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孕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的基于尿道的药物疗法。