nAChR sensitivity and individual differences in drug abuse vulnerability

nAChR 敏感性和药物滥用脆弱性的个体差异

• 批准号: 9118921
• 负责人: Mark J Ferris
• 金额: $ 24.61万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118921
• 关键词: Acetylcholine; Acute; Affect; Animal Model; Animals; Area; Behavior; Brain; Cell Nucleus; Cessation of life; Chronic; Cocaine; Cocaine Dependence; Collection; Cues; Data; Dependence; Detection; Development; Dopamine; Drug abuse; Environment; Exposure to; Funding; Goals; High Pressure Liquid Chromatography; Hospitalization; Illicit Drugs; Imprisonment; Individual; Individual Differences; Infusion procedures; Intake; Lead; Link; Measures; Mecamylamine; Mentors; Microdialysis; Monitor; Nicotine; Nicotinic Receptors; Nucleus Accumbens; Pharmaceutical Preparations; Phase; Predisposing Factor; Preventive measure; Public Health; Rattus; Regulation; Research; Research Personnel; Research Training; Rewards; Risk Factors; Rodent; Role; Safety; Scanning; Self Administration; Self-Administered; Series; Signal Transduction; Societies; Sucrose; System; Technical Expertise; Testing; Time; United States; Ventral Tegmental Area; Vulnerable Populations; addiction; behavior measurement; career development; cholinergic; cost; drug abuse vulnerability; experience; neurobiological mechanism; neurochemistry; novel; programs; research study; response

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.

描述（由申请人提供）：K99/R00研究和培训计划将有两个目的。第一是通过以下方式提供实质性的职业发展：1)扩展研究者的专业领域，包括乙酰胆碱系统及其与中脑边缘多巴胺的相互作用；2)扩展研究者的技术技能，包括啮齿动物自我给药和自由活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；3)启动一项研究计划，通过专业发展和收集主要研究的初步数据（R01）资助，使研究独立。第二个相应的目的是表征药物自我给药行为习得的个体差异的神经生物学机制。通过一系列神经化学和行为测量，包括微透析、高效液相色谱、麻醉和自由活动动物的伏安法，以及自我给药，我们将表征初级奖励和条件线索诱发的多巴胺释放的大小以及相应的自我给药可卡因和自然奖励倾向的个体差异。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，从药理学上操纵腹侧被皮层（VTA）和伏隔核（NAc）尼古丁乙酰胆碱受体（nAChRs），以证明它们调节奖励和提示诱发多巴胺瞬变的能力的个体差异。我们提出解释个体在药物自我给药行为习得上的差异的潜在机制在于VTA和NAc nachr调节快速和慢速习得动物NAc壳中多巴胺释放的能力不同。