Escalating Cocaine Self-Administration: NMDA Mechanisms

说明（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，重度吸毒者可卡因消费量的增加推动了美国对可卡因的需求，并对个人和公共健康造成了更大的威胁。事实上，DSM-IV关于物质依赖的七项标准中有四项与使用者消耗的药物量有关。尽管动物模型（如药物自我给药过程）对我们理解药物使用背后的行为和神经生物学机制做出了巨大贡献，但药物依赖的这一关键方面（增加消耗）尚未被广泛建模或探索。然而，最近有一种动物模型被描述，在这种模型中，老鼠在每天的自我给药过程中获得6小时的可卡因，随着时间的推移，它们的药物消耗量会增加。这种行为适应（消耗增加）在标准的短时间（1或2小时）自我给药过程中观察不到。基于大鼠对一系列剂量可卡因的反应变化，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描述在这些条件下增加可卡因消费量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谷氨酸能活动。此外，对可卡因运动刺激作用的致敏涉及n -甲基- d -天冬氨酸（NMDA）谷氨酸受体的激活，当大鼠接受NMDA受体拮抗剂治疗时，这种作用被阻止。因此，可卡因消费增加背后的神经生物学机制可能与其他形式的可卡因致敏机制相似。这一建议的目的是确定当老鼠被允许长期接触可卡因时，可卡因消耗量增加的根本变化的性质。本申请中提出的实验验证了一种假设，即这种行为适应（增加消耗）的机制与其他形式的适应重复药物暴露（如耐受性和致敏性）的机制相似。具体来说，这一建议批判性地验证了一个假设，即从稳定的可卡因摄入到增加的可卡因消耗的转变涉及到NMDA受体的激活，并且当大鼠在长时间的可卡因自我给药过程中长期接受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.