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，每经历一次快速而强烈的可卡因激增，进一步吸毒的风险就会增加，吸食可卡因的可能性就会增加。虽然众所周知，大鼠的可卡因摄入量呈现快速上升的负荷期，但大多数可卡因成瘾的啮齿动物模型都专注于维持阶段，并探索了长时间获得可卡因的影响。一般的假设是，更多的药物暴露和高摄入量会产生成瘾的表型。这笔拨款挑战了这一前提。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摄入模式向暴饮式摄入模式的转变。我们的数据显示，导致药物水平飙升的自我给药程序会更有力地增加药物摄入量，并显著增加自我给药的动机。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。这项拨款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将检验这样一种假设，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量和反应动机(通过累进比率时间表衡量)的重要决定因素。特定目标1还将检验这样一种假设，即可卡因自身给药受到内源性昼夜节律影响的调节，以及增加可卡因水平可以扰乱这一重要的生理控制机制。我们的理论观点在很大程度上依赖于对可卡因在大脑中浓度的建模，对我们来说，检验和验证该模型背后的假设变得很重要。特定目标2将使用自我给药程序验证动力学模型，并将检查可卡因消费对细胞外可卡因和多巴胺参数的影响。我们将针对具体目标开发一种分离食欲和消耗性反应的方法。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费，在另一个杠杆上研究获得可卡因的动机。通过使用公关时间表，并操纵超时和一天中的时间，该程序将使我们能够测试关于大脑水平可卡因、寻求药物和吸毒之间的关系的假设。 公共卫生相关性：这项拟议的工作有望为成瘾过程中涉及的神经机制提供新的见解。人们如何在成瘾过程的不同阶段取得进展是由药物使用模式决定的，或者至少是预测的。这些研究将使用动物模型更好地了解大剂量可卡因和快速上升的大脑水平如何影响特定的神经靶点，并可能导致新的治疗策略，以抑制吸毒的兴趣。

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. PUBLIC HEALTH RELEVANCE: The proposed work is expected to provide new insights into neural mechanisms involved in the addiction process. How people progress through various stages of the addiction process is determined, or at least predicted, by the pattern of drug use. These studies will use an animal model to a better understanding of how large doses and fast rising brain levels of cocaine affect specific neural targets and may potentially lead to new therapeutic strategies to dampen interest in drug taking.