Eph Receptors and Behavioral Sensitization to Cocaine

描述（由申请人提供）： 滥用可卡因等精神兴奋剂是一个重大的社会经济问题。阐明相关的药物诱导的行为效应的细胞和分子决定因素后，反复精神兴奋剂管理是至关重要的发现新的疗法来治疗这种疾病。大量证据表明，与重复服用可卡因相关的神经生理学适应有助于药物渴望和成瘾。此外，药物诱导的神经元可塑性在精神兴奋剂给药后的细胞变化中是明显的。研究药物诱导的神经元可塑性的细胞和分子机制不仅有助于我们理解药物成瘾和渴求，也有助于我们理解中枢神经系统可塑性的神经机制。最近，肝配蛋白及其受体被证明会影响中脑多巴胺系统的可塑性，该系统介导对精神兴奋剂的行为敏化的发展和长期表达。本研究的目的是阐明Eph受体在可卡因诱导的可卡因行为敏化中的作用。这项研究的第一个目标是确定急性和重复可卡因给药对中脑和黑质纹状体多巴胺通路中Eph受体水平的影响。最后，Eph受体对可卡因诱导的行为敏化的起始和表达的影响将通过使用反义寡核苷酸在体内抑制其表达来研究。

DESCRIPTION (provided by applicant): Abuse of psychostimulants such as cocaine is a major socioeconomic problem. Elucidating the cellular and molecular determinants of the associated drug-induced behavioral effects following repeated psychostimulant administration is paramount toward discovering novel therapeutics to treat this disease. A large body of evidence demonstrates that the neurophysiological adaptations associated with repeated cocaine administration contribute to drug craving and addiction. Furthermore, drug-induced neuronal plasticity is evident in cellular changes following psychostimulant administration. Studying the cellular and molecular mechanisms underlying drug-induced neuronal plasticity will not only help us understand drug addiction and craving but also the neural mechanisms underlying plasticity in the central nervous system. Recently, ephrins and their receptors were shown to influence plasticity in the mesotelencephalic dopamine systems, which mediate both the development and long-term expression of behavioral sensitization to psychostimulants. The goal of this research proposal is to elucidate the role of Eph receptors in cocaine-induced behavioral sensitization to cocaine. The first goal of this proposed research is to determine the effects of acute and repeated cocaine administration on Eph receptor levels in the mesoaccumbal and nigrostriatal dopamine pathways. Lastly, the influence of Eph receptors on the initiation and expression of cocaine-induced behavioral sensitization will be studied by inhibiting their expression in vivo using antisense oligonucleotides.