Rapid DA-Acb signaling in ingestive behaviors

描述（由申请人提供）： 神经递质多巴胺（DA）和延髓核（Acb）中神经元的快速亚秒级信号传导与可卡因寻求行为和一般药物服用密切相关。该职业发展奖将描述DA和Acb细胞对自然刺激的固有反应，以及这些反应如何随着学习，动机和内源性肽作用而变化。该奖项还将用于培训PI最先进的电生理和电化学技术，同时他建立了自己的独立研究路线。在实验1-3中，DA和Acb活性将在两组动物中快速取样，使用：1）在碳纤维微电极上的体内快速扫描循环伏安法（以测量细胞外Acb DA的亚秒级增加）和2）使用长期植入的微丝电极阵列（以测量Acb神经元的电生理活性）。在实验1中，该系统对奖励性（蔗糖）和厌恶性（奎宁）味觉刺激的快速反应将在幼稚的、未经训练的大鼠中进行评估。在实验2中，这个系统在学习提示-促味剂协会的作用将通过在经典条件反射环境刺激之前、期间和之后测定它来确定，以奖励（蔗糖）或厌恶（奎宁）促味剂递送。在实验3中，将通过记录具有（奖励）或不具有（厌恶）钠食欲的大鼠对高渗钠溶液的味道的快速反应来评估该神经系统对激励状态的整合。在实验4中，将在体外脑切片制备中确定影响食物摄入的肽（瘦素、黑皮质素）对Acb中快速DA信号传导的影响。这些肽对快速DA释放的影响将强烈支持研究这些肽不仅用于治疗肥胖症，而且还用于治疗药物成瘾。这些研究将建立一系列促进快速DA-Acb信号传导的自然刺激-为检查药物成瘾相关的异常信号传导奠定基础。

DESCRIPTION (provided by applicant): The rapid, subsecond signaling of the neurotransmitter dopamine (DA) and neurons in the nucleus accumbens (Acb) have been strongly implicated in cocaine seeking behaviors and drug taking in general. This Career Development Award will characterize the innate responses of DA and Acb cell firing to natural stimuli and how the responses change as a function of learning, motivation and endogenous peptide action. The award will also serve to train the PI in state-of-the-art electrophysiological and electrochemical techniques while he establishes his own independent line of research. In Experiements 1-3, DA and Acb activity will be rapidly sampled in two groups of animals using: 1) in vivo fast-scan cyclic voltammetry at carbon-fiber micrelectrodes (to measure subsecond increases in extracellular Acb DA) and 2) using chronically implanted microwire electrode arrays (to measure the electrophysiological activity of Acb neurons). In Experiement 1, the rapid responses of this system to rewarding (sucrose) and aversive (quinine) taste stimuli will be assessed in naive, untrained rats. In Experiment 2, the role of this system in learning cue-tastant associations will be determined by assaying it before, during and after classical conditioning of environmental stimuli to rewarding (sucrose) or aversive (quinine) tastant delivery. In Experiment 3, the integration of motivated state by this neural system will be assessed by recording rapid responses to the taste of a hypertonic sodium solution in rats with (rewarding) or without (aversive) a sodium appetite. In Experiment 4, the impact of peptides that affect food intake (leptin, melancortins) on rapid DA signaling in the Acb will be determined in an in vitro brain slice preparation. Effects of these peptides on rapid DA release would strongly support investigation of the use of these peptides not just in the treatment of obesity but in the treatment of drug addiction as well. These studies will establish the range of natural stimuli that promote rapid DA-Acb signaling - setting the foundation for examining aberrant signaling underlying drug addiction.