nAChR Sensitivity and Individual Differences in Drug Abuse Vulnerability

描述（由申请人提供）：K99/R 00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）将研究者的专业领域扩展到包括乙酰胆碱系统及其与中脑边缘多巴胺的相互作用，2）将研究者的技术技能集扩展到包括啮齿动物自我给药和自由移动动物中的快速扫描循环伏安法，特别是在线索诱发的多巴胺释放的检测中，以及3）发起一项研究计划，通过专业发展和收集主要研究（R 01）资金的初步数据，实现研究独立。第二个相应的目的是表征药物自我给药行为获得个体差异的神经生物学机制。使用一系列的神经化学和行为的措施，包括微透析，高效液相色谱法，伏安法在麻醉和自由移动的动物，自我管理，我们将表征个体差异的幅度的主要奖励和条件线索诱发的多巴胺释放以及相应的倾向，自我管理可卡因和自然奖励。此外，我们将通过急性和慢性给药尼古丁和亚型特异性nAChR拮抗剂，以证明其调节奖赏和线索诱发的多巴胺瞬变的能力的个体差异，来操纵腹侧被盖区（VTA）和延髓核（NAc）烟碱乙酰胆碱受体（nAChR）。我们建议，一个潜在的机制，以解释个体差异收购的药物自我管理的行为驻留在不同的能力，腹侧被盖区和NAc乙酰胆碱受体调节多巴胺释放的外壳中的NAc在快速和缓慢收购的动物。 公共卫生相关性：药物滥用，包括可卡因成瘾，是公共卫生和安全的主要问题，因为它影响到全世界数百万人，导致住院，监禁，甚至死亡。仅在美国，社会成本就达到数千亿美元。这项研究的目的是了解神经化学机制和潜在的危险因素，这些因素导致滥用物质，特别是可卡因的倾向的个体差异，因此最终，这些信息可以用于制定预防措施，以减少弱势群体的药物滥用。

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. PUBLIC HEALTH RELEVANCE: Drug abuse, including cocaine addiction, is a major concern for public health and safety as it affects millions of individuals worldwide, leading to hospitalizations, incarceration, and even death. The cost to society reaches the hundreds of billions in the United States alone. The goal of this research is to understand the neurochemical mechanisms and potential risk factors that contribute to individual differences in propensity to abuse substances, particularly cocaine, so that ultimately, this information can be used to develop preventative measures to reduce drug abuse in vulnerable populations.