Recent advances in imaging technology have begun to indicate that several brain sites, previously shown to be associated with different memory systems, are activated during craving induced by cocaine-associated cues in human subjects. Studies suggest a link between limbic and cortical structures in mediating drug craving and underscore the possible importance of cognitive processes for this and other aspects of drug addiction. The proposed plan is to use a neural systems approach to examine the relationships between different memory systems and addiction-related behavior studied with a second-order schedule of intravenous cocaine and morphine delivery in rats. A second-order schedule of drug delivery measures behaviors thought to be related to drug craving and to drug use. Two complementary projects are proposed. The first project will identify how information from different memory systems regulates addiction-related behavior. Addiction-related behavior will be measured during cocaine maintenance and reinstatement (relapse) that follow a period of drug withdrawal. Bilateral infusions of lidocaine and TTX will be used to temporarily and reversibly block neuronal activity, and the roles of specific sites within the four major memory systems (basolateral amygdala, hippocampus, dorsal striatum and prefrontal cortex) in regulating drug-seeking and drug-consummatory behavior will be compared. The completion of this project may identify the functional mechanisms and anatomical pathways by which cognition and drug craving, use and relapse are connected. In the second project, rats will be maintained on a second-order schedule of cocaine or morphine delivery and their performance on a battery of cognitive tasks will be compared to the performance of drug-yoked and saline-yoked rats. Tasks will include those that target hippocampal, basolateral amygdala, dorsal striatal and prefrontal cortex memory functions. These procedures will isolate the specific consequences of persistent drug self-administration from those of a general pharmacological effect of the drug on cognitive performance. The generality of the effects of addiction related behavior on cognitive performance can be determined by comparing different drugs of abuse which differ in mechanism of action. This project may identify the unique cognitive challenges that face a drug-addicted individual
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