Cocaine, Sigma Receptors and Fra-2

可卡因、Sigma 受体和 Fra-2

• 批准号: 7577784
• 负责人: Rae R Matsumoto
• 金额: $ 17.58万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 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 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7577784
• 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一个合理的药物开发目标。最近的研究结论性地表明，药理学拮抗剂或反义寡核苷酸靶向σ受体防止惊厥，致死，运动兴奋剂，和奖励性质的可卡因在小鼠中。尽管这些研究为sigma受体拮抗剂作为可卡因滥用的潜在新药提供了令人信服的证据，但对其对抗各种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，进行了结合行为药理学方法与cDNA微阵列分析和RT-PCR确认的初步研究，以鉴定与原型α受体拮抗剂BD 1063的行为保护作用相关的基因表达变化。作为这个初步研究的结果，我们确定了fra-2，即时早期基因和转录因子的fos家族的成员，作为BD 1063对可卡因的保护作用的重要介质。我们认为，fra-2相关机制在对可卡因的即时反应和伴随重复可卡因暴露的更持久的变化之间的过渡中起着关键作用。这种假设的可卡因，a受体和fra-2之间的相互作用可以解释a受体拮抗剂在急性和反复暴露于可卡因后对抗一系列行为的能力。为了开始验证我们的假设，R21的具体目标是：1）确定可卡因诱导的Fra-2和CT受体mRNA和蛋白质表达变化之间的时间关系，2）鉴定可卡因诱导的Fra-2和CT受体表达变化发生的脑区域，和3）确定可卡因诱导的Fra-2和cr受体表达的增加与行为敏化的发展之间的时间关系。总之，我们预计这些研究将揭示神经系统在对急性与重复可卡因暴露做出反应时发生转变的新机制。这些信息对于开发新的治疗方法以打击可卡因滥用至关重要。