nAChR Sensitivity and Individual Differences in Drug Abuse Vulnerability

描述(由申请人提供)：K99/R00研究和培训计划将用于两个目的。第一是通过以下方式提供实质性的职业发展：1)扩大研究人员的专业领域，包括乙酰胆碱系统及其与中脑边缘多巴胺的相互作用；2)扩大研究人员的技术技能，包括啮齿动物的自我管理和自由移动动物的快速扫描循环伏安法，特别是在检测线索诱发的多巴胺释放方面；以及3)启动一项研究计划，通过专业发展和收集重大研究(R01)资金的初步数据来实现研究独立性。第二个相应的目的是描述药物自我给药行为获得的个体差异的神经生物学机制。使用一系列神经化学和行为测量方法，包括微透析、高效液相、麻醉和自由活动动物的伏安法，以及自我给药，我们将表征初级奖赏和条件性提示诱发的多巴胺释放的个体差异，以及相应的自我给药可卡因和自然奖赏的倾向。此外，我们将通过急性和慢性给予尼古丁和亚型特异性nAChR拮抗剂，从药理上操纵腹侧被盖区(VTA)和伏核(NAC)的烟碱型乙酰胆碱受体(NAChRs)，以展示它们调节奖赏和暗示诱发的多巴胺瞬变的能力的个体差异。我们认为，解释药物自我给药行为获得的个体差异的潜在机制在于VTA和NAC nAChRs在快速和缓慢获得动物中调节NAC壳中多巴胺释放的不同能力。

DESCRIPTION (provided by applicant): The K99/R00 research and training plan will serve two purposes. The first is to provide substantial career development by: 1) expanding the investigator's area of expertise to include acetylcholine systems and their interaction with mesolimbic dopamine, 2) expanding the investigator's technical skill set to include rodent self-administration and fast scan cyclic voltammetry in freely moving animals, particularly in the detection of cue-evoked dopamine release, and 3) initiating a research program that will lead to research independence through professional development and collection of preliminary data for major research (R01) funding. The second corresponding purpose is to characterize a neurobiological mechanism for individual differences in the acquisition of drug self-administration behavior. Using a series of neurochemical and behavioral measures including microdialysis, HPLC, voltammetry in anesthetized and freely-moving animals, and self-administration, we will characterize individual differences in the magnitude of primary reward and conditioned cue-evoked dopamine release as well as corresponding propensity to self-administer cocaine and natural rewards. In addition, we will pharmacologically manipulate ventral tegmental area (VTA) and nucleus accumbens (NAc) nicotinic acetylcholine receptors (nAChRs) via acute and chronic administration of nicotine and subtype specific nAChR antagonists in order to demonstrate individual differences in their ability to modulate reward and cue-evoked dopamine transients. We propose that an underlying mechanism to explain individual differences in acquisition of drug self-administration behavior resides in the differental ability of VTA and NAc nAChRs to modulate dopamine release in the shell of the NAc in fast and slow acquiring animals.