Cocaine abuse remains a significant societal problem. A central theme of this research program, and the main hypothesis of this renewal application, is that chronic cocaine abuse produces significant changes in CNS gene expression that contribute to clinical issues such as tolerance, sensitization, physical dependence, craving, and withdrawal. Preliminary findings have added to the growing database on cocaine-responsive gene expression in the central nervous system. Experiments are proposed, within the present application, that extend these findings to identify those genes whose expression is altered following an enforced abstinence from cocaine self-administration. To accomplish this, a new behavioral paradigm has been developed in which a binge pattern of cocaine self-administration in rats, followed by a period of abstinence, produces a behavioral sensitization that displays some of the hallmarks of the addictive process in humans. This powerful behavioral model will be examined to identify those genes exhibiting persistent changes in gene expression following cessation of drug administration. The first series of experiments will examine the expression of known cocaine-responsive genes to see if they correlate with the behavioral sensitization. The studies will focus on the nucleus accumbens (core and shell), medial prefrontal cortex, hippocampus, and amygdala as neuroanatomical substrates of the behavioral perturbation. In addition, subsequent studies will concentrate on establishing the temporal course of gene expression to (a) establish the limits of the alterations (how long will they last?), and (b) determine the time at which the changes first become manifest (before or during the abstinence period?). The second series of studies will use new Affymetrix GeneChip technologies (14,280 genes at a time) to identify families of genes that may be coordinately regulated and to identify novel targets of cocaine's effects. The proposed experiments will continue to contribute to our understanding of the role of genomics in establishing and maintaining cocaine addiction.
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