Cocaine, Sigma Receptors and Fra-2

可卡因、Sigma 受体和 Fra-2

• 批准号: 6920553
• 负责人: Rae R Matsumoto
• 金额: $ 21.6万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6920553
• 关键词: behavioral /social science research tag; behavioral habituation /sensitization; brain mapping; cocaine; drug receptors; fos protein; laboratory mouse; polymerase chain reaction; protein localization; protein quantitation /detection; protein structure function; receptor expression; time resolved data; transcription factor; western blottings

The ability of cocaine to interact with a receptors provides a logical medications development target. Recent studies conclusively demonstrate that pharmacological antagonists or antisense oligonucleotides targeting sigma receptors prevent the convulsive, lethal, locomotor stimulant, and rewarding properties of cocaine in mice. Although these studies provide compelling evidence for sigma receptor antagonists as potential new medications for cocaine abuse, the mechanisms that underlie their ability to combat a wide array of behaviors are poorly understood. Therefore, to begin elucidating these protective mechanisms, a preliminary study combining behavioral pharmacological approaches with cDNA microarray analysis and RT-PCR confirmations were performed to identify changes in gene expression that are associated with the behavioral protective actions of BD1063, a prototypic a receptor antagonist. As a result of this preliminary study, we identified fra-2, an immediate early gene and member of the fos family of transcription factors, as an important mediator of the protective actions of BD1063 against cocaine. We propose that fra-2 related mechanisms are critically involved in the transition between the immediate response to cocaine and the more persistent changes that accompany repeated cocaine exposure. This hypothesized interaction between cocaine, a receptors, and fra-2 may explain the ability of a receptor antagonists to combat an array of behaviors following acute, as well as repeated, exposure to cocaine. To begin validating our hypothesis, the specific aims of this R21 are to: 1) determine the temporal relationship between cocaineinduced changes in fra-2 and CT receptor mRNA and protein expression, 2) identify the brain regions where cocaine-induced changes in Fra-2 and CT receptor expression occur, and 3) determine the temporal relationship between cocaine-induced increases in Fra-2 and cr receptor expression and the development of behavioral sensitization. Together, we anticipate that these studies will uncover new mechanisms that underlie the transition of the nervous system as it responds to acute vs. repeated cocaine exposures. Such information will be critical for developing novel therapies to combat cocaine abuse.

可卡因与受体相互作用的能力提供了逻辑药物开发目标。最近的研究最终表明，靶向Sigma受体的药理学拮抗剂或反义寡核苷酸可防止可卡因在小鼠中可卡因的抽搐，致命，运动刺激剂和奖励性能。尽管这些研究为Sigma受体拮抗剂提供了令人信服的证据，作为可卡因滥用的潜在新药物，但对抗击广泛行为的能力的机制知之甚少。因此，为了开始阐明这些保护机制，进行了一项将行为药理方法与cDNA微阵列分析和RT-PCR确认结合的初步研究，以识别与BD1063的行为保护作用相关的基因表达变化，这是一种原型A受体拮抗剂。这项初步研究的结果是，我们确定了FRA-2是早期基因，也是FOS转录因子家族的成员，是BD1063对可卡因的保护作用的重要介体。我们建议，与FRA-2相关的机制与可卡因的直接反应与重复可卡因暴露伴随的更持续变化之间的过渡至关重要。可卡因，受体和FRA-2之间的这种假设的相互作用可能解释了受体拮抗剂在急性后与可卡因暴露在急性后对抗一系列行为的能力。要开始验证我们的假设，该R21的具体目的是：1）确定可卡因诱导的FRA-2和CT受体mRNA和蛋白质表达的变化之间的时间关系，2）确定可卡因诱导的大脑区域，其中可卡因诱导的FRA-2和CT受体表达中可卡因诱导的变化，以及在Cocain诱导的fra-fra-fra-2中的时间之间的变化，以及3）确定了在FRA和FRA中的表达之间的变化。我们共同预计，这些研究将发现新机制，这些机制是神经系统对急性与重复可卡因暴露的反应时的过渡。此类信息对于开发新型疗法来打击可卡因滥用至关重要。