Cocaine, Sigma Receptors and Fra-2

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。最近的研究结果表明，针对Sigma受体的药理拮抗剂或反义寡核苷酸可以阻止可卡因对小鼠的惊厥、致命性、运动刺激性和奖励性。尽管这些研究为Sigma受体拮抗剂作为治疗可卡因滥用的潜在新药提供了令人信服的证据，但它们对抗广泛行为的机制尚不清楚。因此，为了开始阐明这些保护机制，我们进行了一项结合行为药理学方法、基因芯片分析和RT-PCR验证的初步研究，以确定与A受体拮抗剂原型BD1063的行为保护作用相关的基因表达的变化。作为这项初步研究的结果，我们确定FRA-2是一个即刻早期基因，也是FOS转录因子家族的成员，是BD1063对可卡因保护作用的重要中介。我们认为，fra-2相关机制在对可卡因的即刻反应和伴随可卡因反复暴露而来的更持久的变化之间的转换中起着关键作用。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和重复接触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和蛋白表达变化之间的时间关系；2)确定可卡因诱导的Fra-2和CT受体表达变化的大脑区域；以及3)确定可卡因诱导的Fra-2和cr受体表达增加与行为敏化发展之间的时间关系。总而言之，我们预计这些研究将揭示神经系统在对急性可卡因暴露做出反应时发生转变的新机制。这些信息将对开发打击可卡因滥用的新疗法至关重要。

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.