Escalating Cocaine Self-Administration: NMDA Mechanisms

描述（由申请人提供）：可卡因滥用对个人和公共健康构成严重威胁。 据认为，可卡因重度使用者可卡因消费量的增加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的七个物质依赖标准中有四个与用户消耗的药物量有关。虽然动物模型（如药物自我给药程序）极大地促进了我们对药物使用的行为和神经生物学机制的理解，但药物依赖的这一关键方面（增加消费）尚未得到广泛的建模或探索。然而，最近已经描述了一种动物模型，其中大鼠在每日自我给药会话中获得6小时的可卡因，随着时间的推移增加其药物消耗。这种行为适应（增加消费）没有观察到标准的短期访问（1或2小时）自我管理程序。基于大鼠对一系列剂量的可卡因的反应的变化，这些剂量的可卡因是在长期获得可卡因的自我给药阶段之后发生的，这种行为适应被描述为药物致敏的一个例子。不幸的是，几乎没有可用的信息来描述在这些条件下与可卡因消费增加相关的神经生物学相关性。然而，有证据表明，可卡因的强化和行为效应涉及神经元活动。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，并且当用NMDA受体拮抗剂处理大鼠时被阻止。因此，可卡因消费增加的神经生物学机制可能与其他形式的可卡因致敏的神经生物学机制相似。本提案的目的是确定当允许老鼠长期接触可卡因时可卡因消费量增加的变化的性质。本申请中提出的实验检验了这样的假设，即这种行为适应（增加消费）的基础机制与重复药物暴露的其他形式适应（如耐受性和致敏性）的基础机制相似。具体而言，该提案严格测试的假设，从稳定的可卡因摄入量增加可卡因消费量的过渡涉及激活NMDA受体，这种行为适应是可以预防的，当大鼠长期接受NMDA受体拮抗剂在整个扩展访问可卡因自我管理会话。

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.