Escalating Cocaine Self-Administration: NMDA Mechanisms

描述(申请人提供)：可卡因滥用对个人和公共健康构成严重威胁。毒品重度使用者的可卡因消费增加被认为推动了美国对可卡因的需求，并导致对个人和公共健康的更大威胁。事实上，DSM-IV关于物质依赖的七个标准中有四个与使用者的药物消耗量有关。虽然动物模型(如药物自我给药过程)对我们理解药物使用的行为和神经生物学机制做出了很大贡献，但药物依赖(增加消费)的这一关键方面还没有被广泛地模拟或探索。然而，最近描述了一种动物模型，在该模型中，每天自我给药6小时的大鼠的药物消耗量随着时间的推移而增加。这种行为适应(增加的消耗)在标准的短时间(1或2小时)自我给药程序中没有观察到。根据大鼠在长时间使用可卡因自我给药后对一系列可卡因反应的变化，这种行为适应被描述为药物敏化的一个例子。不幸的是，几乎没有可用的信息来描述在这些情况下与增加可卡因消费相关的神经生物学相关性。然而，有证据表明，可卡因的强化作用和行为效应涉及谷氨酸能活动。此外，对可卡因的运动刺激作用的敏化涉及N-甲基-D-天冬氨酸(NMDA)谷氨酸受体的激活，当用NMDA受体拮抗剂处理大鼠时，这一作用被阻止。因此，导致可卡因消费增加的神经生物学机制可能与其他形式可卡因敏化的神经生物学机制类似。这项提议的目的是确定当允许大鼠长期接触可卡因时，导致可卡因消费增加的变化的性质。在这项申请中提出的实验测试了这样一个假设，即这种行为适应(增加消费)的机制与其他形式的对重复药物暴露的适应类似，如耐受性和敏化。具体地说，这项建议对从稳定的可卡因摄入量到增加的可卡因摄入量涉及NMDA受体激活的假设进行了批判性测试，并且当大鼠在延长给药期间长期接受NMDA受体拮抗剂时，这种行为适应是可以预防的。

DESCRIPTION (provided by applicant): Cocaine abuse represents a serious threat to personal and public health. The increased consumption of cocaine in heavy users of the drug is thought to drive demand for cocaine in the United States and lead to greater threats to personal and public health. Indeed, four of the seven DSM-IV criteria for Substance Dependence relate to the amount of drug consumed by a user. Although animal models (such as the drug self-administration procedure) have contributed greatly to our understanding of the behavioral and neurobiological mechanisms that underlie drug use, this critical aspect of drug dependence (increased consumption) has not been extensively modeled or explored. Recently, however, an animal model has been described in which rats given 6-hour access to cocaine in daily self-administration sessions increase their drug consumption over time. This behavioral adaptation (increased consumption) is not observed with standard short-access (1 or 2 hr) self-administration procedures. Based on the changes in rats' responding for a range of doses of cocaine that follow extended-access cocaine self-administration sessions, this behavioral adaptation has been described as an example of drug sensitization. Unfortunately, there is virtually no information available that describes the neurobiological correlates associated with increased cocaine consumption under these conditions. There is evidence, however, that the reinforcing and behavioral effects of cocaine involve glutamatergic activity. Further, sensitization to the locomotor stimulating effects of cocaine involves activation of N-methyl-D-aspartate (NMDA) glutamate receptors, and is prevented when rats are treated with NMDA receptor antagonists. It is possible, therefore, that the neurobiological mechanisms that underlie increased cocaine consumption are similar to those that underlie other forms of cocaine sensitization. The purpose of this proposal is to determine the nature of the changes that underlie the increases in cocaine consumption that occur when rats are permitted long access to cocaine. The experiments proposed in this application test the hypothesis that the mechanisms that underlie this behavioral adaptation (increased consumption) are similar to those that underlie other forms of adaptation to repeated drug exposure, such as tolerance and sensitization. Specifically, this proposal critically tests the hypothesis that the transition from stable cocaine intake to increased cocaine consumption involves activation of NMDA receptors, and that this behavioral adaptation is preventable when rats receive chronically an NMDA receptor antagonist throughout extended-access cocaine self-administration sessions.