The proposed experiments are directed toward an understanding of the neuroanatomical and neurochemical substrates of the long-lasting behavioral, cognitive, physiological, and neurobiological consequences of chronic cocaine abuse. This phenomenon, called behavioral sensitization is a complex process that can be significantly influenced by a number of non-pharmacological variables including the presence of conditioned environmental cues. Conditioned effects are also thought to be important determinants of human drug abuse, particularly in such phenomena as drug craving and relapse. The effects of conditioned environmental cues on repeated cocaine administration most likely are mediated by neuronal circuits different from those that mediate the unconditioned consequences of repeated administration. The proposed experiments are designed to characterize further the neuroanatomical substrates of behavioral sensitization with a specific focus on the influence of conditioned cues in this process. Specifically, the quantitative 2-[14C]deoxyglucose autoradiographic method will be used to identify in rats 1) the brain regions that mediate cocaine-induced behavioral sensitization in the presence and absence of conditioned environmental stimuli, 2) the dose-dependent effects of repeated cocaine administration, 3) the time course of development of conditioned behavioral sensitization, and 4) the persistence of the effects of conditioned behavioral sensitization following withdrawal from cocaine treatment. A second goal of the proposed studies is to determine the neurochemical changes that underlie the changes in functional activity observed in the metabolic mapping studies. First, quantitative receptor autoradiography will be used to measure alterations in dopaminergic and opioid receptor systems. Measurements of receptor density will be made in the same animals used in the 2-deoxyglucose studies, permitting the systematic evaluation of the effects of dose, duration of treatment, presence of conditioned cues, and length of time following withdrawal from drug treatment on receptor number. Second, in vivo microdialysis will be used to measure the effects of repeated cocaine administration in the presence of conditioned environmental cues on concentrations of extracellular dopamine in the nucleus accumbens. The relationship between dopamine concentrations and rates of glucose utilization in this nucleus will be investigated by combining 2-deoxyglucose and in vivo microdialysis measures in rats chronically treated with cocaine. These studies have important implications for the understanding of the long term sequelae of chronic cocaine abuse. Furthermore, they will provide a more comprehensive analysis of the role of conditioned environmental cues in chronic drug abuse and may provide a more extensive basis for the development of behavioral and pharmacological strategies for treatment.
