During the first three years of funding, we used proton and phosphorus magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (fMRI) techniques, to document important changes in brain chemistry and hemodynamics following acute cocaine administration. We have also used fMRI methods to demonstrate changes in cerebral metabolism associated with cocaine cue-induced craving. Studies which merge electroencephalography (EEG) with fMRI to evaluate task- and drug-induced effects on cortical electrical activity are also underway. Important accomplishments include the documentation of cocaine-induced vasospasm and decreased cerebral blood volume following acute cocaine administration, the demonstration that exposure to cocaine cues leads to changes in cerebral metabolism which can be detected using blood oxygen level dependent (BOLD) fMRI, and the identification of a novel treatment strategy for cocaine dependent individuals. This competing continuation requests five years of funding to pursue a series of studies on the acute and chronic effects of cocaine on the human brain. In this application, we will continue to study the effects of acute cocaine administration, taking advantage both of insights derived from our prior work as well as advances in magnetic resonance methods. As an important new direction for this research effort, based on findings obtained during the current funding period, we also propose investigations on the effects of chronic cocaine use and early abstinence on the brain. Relatively few studies to date have focused on changes in brain chemistry or metabolism associated with recovery from cocaine dependence, despite their importance for efforts to develop more effective therapies. We propose a total of eight separate studies, involving 392 subjects who will complete 524 magnetic resonance examinations. These studies are designed to investigate the neuroanatomic bases of cocaine-induced euphoria and cue-induced craving, processes which contribute to chronic cocaine use and dependence. As pharmacologic strategies for the treatment of cocaine abuse and dependence include the use of dopaminergic and GABAergic agents, we will assess changes in retinal dopamine metabolism and brain GABA concentrations in cocaine-dependent subjects. This research will also evaluate whether acute cocaine administration is associated with transient cerebral ischemia and whether chronic cocaine use leads to neuronal death and/or diminished cerebrovascular reserve.
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