Cocaine/nicotine action on acetylcholine receptors

描述（由申请人提供）： 该项目的目标是确定两个 滥用的药物，尼古丁和可卡因，与神经元烟碱相互作用， 乙酰胆碱受体（nAChR）在外周和中枢神经系统。 可卡因通过多巴胺转运发挥其欣快、成瘾的性质 系统，但它的一些毒性作用是由神经元的亚型介导的。 nAChRs。nAChRs调节许多中枢神经系统之间的信号传递 神经元和神经肌肉接头，尼古丁和可卡因都影响 它们的功能。文献中的报告表明，可卡因和其他 局部麻醉剂在心室内给药时， 尼古丁的行为和药理作用。我们已经鉴定出RNA 与nAChR相互作用并可以减轻 可卡因的作用而不影响受体功能。同样，几个 可卡因衍生物已被鉴定具有类似的性质。的一个目的 该建议将这些研究扩展到各种神经元nAChR 亚型，以开发特定的药物，将减轻影响， 可卡因和（-）尼古丁的抑制作用。第二组研究 将建立在我们以前的工作表明，可卡因的影响是 在神经元nAChR亚型中至少有两个不同的位点介导。 稳定转染的细胞系和新开发的转染系统将在 用于研究神经元nAChR的各种亚型的瞬时动力学， 为了更详细地表征可卡因的结合位点， 尼古丁。快速混合技术和激光脉冲光解将用于 提供μ S到ms时间尺度上的时间分辨率。分子 机制，包括尼古丁浓度的知识， 可卡因影响特定的nAChRs，将为基于机制的设计提供基础 减轻药物的某些作用， 自身产生有害影响。所获得的知识预计将 有助于合理对待数以百万计的个人， 受可卡因和尼古丁的影响

DESCRIPTION (provided by applicant): The goal of this project is to determine the molecular mechanism by which two abused drugs, nicotine and cocaine, interact with neuronal nicotinic acetyicholine receptors (nAChRs) in the peripheral and central nervous systems. Cocaine exerts its euphoric, addictive nature through the dopamine transport system, but some of its toxic effects are mediated by subtypes of neuronal nAChRs. nAChRs regulate signal transmission between many central nervous system neurons and at the neuromuscular junction, and both nicotine and cocaine affect their function. Reports in the literature have suggested that cocaine and other local anesthetics, when administered intraventricularly, are antagonistic to the behavioral and pharmacological effects of nicotine. We have identified RNA sequences (RNA aptamers) that interact with nAChRs and can alleviate the effects of cocaine without affecting receptor function. Likewise, several cocaine derivatives have been identified with similar properties. One aim of this proposal is to extend these studies to a variety of neuronal nAChR subtypes in order to develop specific agents that will alleviate the effects of cocaine and the inhibitory effects of (-)nicotine. The second group of studies will build on our previous work indicating that the effects of cocaine are mediated by at least two sites which differ among neuronal nAChR subtypes. Stably transfected cell lines and a newly developed transfection system will be used to study the transient kinetics of various subtypes of neuronal nAChRs in order to characterize in more detail the binding sites for cocaine and nicotine. Rapid mixing techniques and laser-pulse photolysis will be used to provide temporal resolution on the muS to ms timescale. The molecular mechanism, including knowledge of the concentration at which nicotine and cocaine affect specific nAChRs, will provide a basis for mechanism-based design of therapeutic agents that alleviate some effects of the drugs without themselves having deleterious effects. The knowledge gained is expected to contribute to the rational treatment of the millions of individuals adversely affected by cocaine and nicotine.