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.
