Animal Models of Cocaine Addiction

可卡因成瘾的动物模型

• 批准号: 8640124
• 负责人: SARA RAULERSON JONES
• 金额: $ 26.64万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8640124
• 关键词: Affect; Animal Model; Animals; Appearance; Brain; Circadian Rhythms; Clinical; Cocaine; Cocaine Dependence; Consumption; Data; Dopamine; Dose; Drug Exposure; Drug usage; Goals; Grant; Height; Injection of therapeutic agent; Intake; Kinetics; Lead; Literature; Maintenance; Measurement; Measures; Methods; Microdialysis; Modeling; Motivation; Neurobiology; Pattern; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Physiological; Price; Procedures; Process; Protocols documentation; Published Comment; Rattus; Risk; Rodent Model; Schedule; Self Administration; Self-Administered; Speed; Staging; Testing; Time; Work; addiction; design; dopamine system; dopamine transporter; experience; extracellular; head-to-head comparison; insight; interest; neuromechanism; novel therapeutics; relating to nervous system; research study; response; uptake

DESCRIPTION (provided by applicant): The clinical literature has emphasized that the abuse potential of cocaine is related to its speed of onset and that each time a person experiences a rapid and intense cocaine rush there is an increased risk of further drug taking and an increased likelihood of addition. While it is well known that cocaine intake in rats shows a fast- rising loading phase, most rodent models of cocaine addiction instead have focused on the maintenance phase and have explored the effects of long access sessions. The general assumption is that more drug exposure and high intake produces an addicted phenotype. This grant challenges that premise. Our hypothesis is that brief episodes (eg. 5 min) of intense drug use are sufficient to cause a transition from recreational to binge-like patterns of intake. Our data show that self-administration procedures that engender spiking drug levels produce a more robust escalation of drug intake and a dramatic increase in the motivation to self- administer cocaine. Our hypothesis is that the number of 'spikes' (or loading phases) have a much greater impact on the addiction process than the maintenance phase or total drug intake. The experiments proposed in this grant are designed to confirm, extend and validate our initial findings. Specific Aim 1 will test the hypothesis that the number of spikes, the change in spike height and the rise time of each spike is an important determinant of escalation of drug intake and the motivation to response (as measured by a progressive ratio schedule). Specific Aim 1 will also test the hypothesis that cocaine self-administration is regulated by an endogenous circadian influence and that spiking cocaine levels can dysregulate this important physiological control mechanism. Our theoretical viewpoint draws heavily on modeling of cocaine concentrations in brain and it becomes important for us to examine and validate the assumptions underlying the model. Specific Aim 2 will validate the kinetic model using self-administration procedures and will examine the effects of cocaine consumption on extracellular cocaine and dopamine parameters. A method for separating appetitive and consummatory responding will be developed in Specific Aim 3. A two lever procedure will allows us to study cocaine consumption on one lever and the motivation to gain access to cocaine on the other lever. By using a PR schedule and manipulating timeouts and time of day the procedure will enable us to test hypotheses regarding the relationship between brain levels cocaine, drug seeking and drug taking.

描述（由申请人提供）：临床文献强调，可卡因的滥用潜力与其起效速度有关，每次一个人经历快速而强烈的可卡因热潮时，进一步吸毒的风险就会增加，并且吸毒的风险也会增加。添加的可能性。众所周知，大鼠的可卡因摄入量表现出快速上升的负荷阶段，但大多数可卡因成瘾啮齿动物模型却侧重于维持阶段，并探索了长时间摄入的影响。一般的假设是更多的药物接触和高摄入量会产生成瘾表型。这笔赠款挑战了这一前提。我们的假设是，短暂的剧烈吸毒（例如 5 分钟）足以导致从娱乐性吸毒模式转变为暴饮暴食模式。我们的数据表明，导致药物水平飙升的自我给药程序会导致药物摄入量更强劲地增加，并显着增加自我给药可卡因的动机。我们的假设是，“尖峰”（或加载阶段）的数量对成瘾过程的影响比维持阶段或总药物摄入量大得多。这笔资助中提出的实验旨在确认、扩展和验证我们的初步发现。具体目标 1 将检验以下假设：尖峰数量、尖峰高度变化和每个尖峰的上升时间是药物摄入量增加和反应动机（通过渐进比例表衡量）的重要决定因素。具体目标 1 还将检验以下假设：可卡因自我给药受内源性昼夜节律影响调节，并且可卡因水平升高可能会失调这一重要的生理控制机制。我们的理论观点很大程度上依赖于大脑中可卡因浓度的建模，对我们来说检查和验证模型背后的假设变得很重要。具体目标 2 将使用自我管理程序验证动力学模型，并将检查可卡因消耗对细胞外可卡因和多巴胺参数的影响。具体目标 3 将开发一种区分食欲反应和完成反应的方法。双杠杆程序将使我们能够研究一个杠杆上的可卡因消费量和另一个杠杆上获取可卡因的动机。通过使用 PR 时间表并操纵超时和一天中的时间，该程序将使我们能够测试有关大脑水平可卡因、寻求毒品和吸毒之间关系的假设。