Animal Models of Cocaine Addiction

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的速度有关，并且每次一个人经历快速和强烈的可卡因冲动时，进一步服用药物的风险增加，并且增加了增加的可能性。虽然众所周知，大鼠的可卡因摄入量显示出快速上升的负荷阶段，但大多数可卡因成瘾的啮齿动物模型都专注于维持阶段，并探索了长时间接触的影响。一般的假设是，更多的药物暴露和高摄入量产生成瘾表型。这项拨款挑战了这个前提。我们的假设是，短暂的插曲(例如：5分钟的高强度吸毒足以导致从娱乐性到暴饮暴食的摄入模式的转变。我们的数据显示，自我给药过程导致药物水平飙升，从而使药物摄入更加强劲，并使自我给药的动机急剧增加。我们的假设是，“峰值”（或加载阶段）的数量对成瘾过程的影响要比维持阶段或总药物摄入量大得多。本拨款中提出的实验旨在证实、扩展和验证我们的初步发现。具体目标1将检验这样一个假设，即尖峰的数量、尖峰高度的变化和每个尖峰的上升时间是药物摄入增加和反应动机的重要决定因素（通过递进比率表测量）。Specific Aim 1还将测试可卡因自我给药受内源性昼夜节律影响调节的假设，可卡因水平的飙升会使这一重要的生理控制机制失调。我们的理论观点在很大程度上依赖于大脑中可卡因浓度的建模，对我们来说，检验和验证模型背后的假设变得很重要。具体目标2将使用自我给药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。将在具体目标3中开发一种分离食欲反应和圆满反应的方法。双杠杆程序将使我们能够在一个杠杆上研究可卡因消费，在另一个杠杆上研究获得可卡因的动机。通过使用PR时间表和操纵暂停时间和一天中的时间，这个过程将使我们能够测试关于大脑水平可卡因，药物寻求和药物服用之间关系的假设。

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.