Rapid DA-Acb signaling in ingestive behaviors

描述(由申请人提供)： 神经递质多巴胺(DA)和伏核(ACB)神经元的快速、亚秒信号与可卡因寻找行为和吸毒密切相关。这一职业发展奖将描述DA和ACB细胞对自然刺激的固有反应，以及这些反应如何作为学习、动机和内源性多肽作用的函数发生变化。该奖项还将用于在他建立自己的独立研究领域的同时，对PI进行最先进的电生理和电化学技术方面的培训。在实验1-3中，两组动物的DA和ACB活性将被快速采样：1)在活体碳纤维微电极上的快速扫描循环伏安法(以测量细胞外ACB DA的亚秒增加)和2)使用长期植入的微线电极阵列(以测量ACB神经元的电生理活动)。在实验1中，这个系统对奖励(蔗糖)和厌恶(奎宁)味觉刺激的快速反应将在幼稚的未受过训练的大鼠身上进行评估。在实验2中，这个系统在学习线索-味觉联系中的作用将通过在经典环境刺激对奖赏(蔗糖)或厌恶(奎宁)味觉传递的条件作用之前、期间和之后进行分析来确定。在实验3中，通过记录有(奖赏)或没有(厌恶)钠胃口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动机状态的整合。在实验4中，将在体外脑片制备中确定影响食物摄取的多肽(瘦素、黑素皮质素)对ACB中快速DA信号的影响。这些多肽对DA快速释放的影响将有力地支持这些多肽不仅用于治疗肥胖症，而且还用于治疗药物成瘾的研究。这些研究将建立促进快速DA-ACB信号的自然刺激范围-为检查药物成瘾的异常信号奠定基础。

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.