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发作速度有关，并且每次一个人都会迅速而强烈的可卡因匆忙急忙，就会增加进一步服用药物的风险和增加的可能性。众所周知，大鼠可卡因的摄入量显示出快速升高的加载阶段，但大多数可卡因成瘾的啮齿动物模型都集中在维护阶段，并探索了长访问会话的影响。一般的假设是，更多的药物暴露和高摄入量会产生上瘾的表型。这项赠款挑战前提。我们的假设是，突然使用的简短发作（例如5分钟）足以引起从休闲到暴饮暴食的过渡。我们的数据表明，产生尖峰药物水平的自我管理程序会导致药物摄入量的升级和自我管理可卡因动机的急剧增加。我们的假设是，与维持阶段或总药物摄入相比，“尖峰”（或加载阶段）的数量对成瘾过程的影响要大得多。该赠款中提出的实验旨在确认，扩展和验证我们的初始发现。具体目标1将检验以下假设：尖峰的数量，尖峰高度的变化和每个尖峰的上升时间是药物摄入量升级和反应动机的重要决定因素（按渐进比率时间表来衡量）。具体目标1还将检验以下假设：可卡因自我给药受到内源性昼夜节律的调节，而尖峰可卡因水平会使这种重要的生理控制机制失调。我们的理论观点大大借鉴了大脑中可卡因浓度的建模，对我们而言，检查和验证模型基础的假设变得很重要。特定的目标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。在特定的目标3中将开发一种分离开胃态和完整响应的方法。两个杠杆程序将使我们能够在一个杠杆上研究可卡因的消耗，并在另一个杠杆上使用可卡因的动机。通过使用PR计划并操纵超时和一天中的时间，该程序将使我们能够检验有关可卡因，寻求药物和药物的脑部关系之间关系的假设。