FMRI STUDY OF CNS PHYSIOLOGY DURING COCAINE RESPONSE

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DESCRIPTION (Applicant's Abstract): This proposal, "fMRI Study of Physiological Couplings During Cocaine Response", is submitted in response to the NIDA program anouncement for Mentored Research Scientist Development Awards (K01). The Candidate seeks to gain training in the neurobiology of drug abuse while contributing research that enhances our understanding of cocaine-induced changes in brain physiology and the interpretation of fMRI signal in terms of those changes. With its unique combination of high spatial and temporal resolution, functional brainmapping by magnetic resonance imaging (fMRI) has great potential to contribute to our understanding of the neurobiology of drug addiction. The early fMRI experience in acute drug studies suggests that only the T2* variants of fMRI blood oxygenation level dependent (BOLD) signal and CBV-weighted signal - have the functional sensitivity to detect focal activation in small brain regions due to drug stimuli in individual subjects. The uncertain interpretation of BOLD signal and CBV in terms of perfusion, the best hemodynamic predictor of metabolism, remains a significant issue. This proposal addresses one part of the multi-step link between neuronal activity and fMRI signal - the relationship between fMRI signal and underlying metabolic and hemodynamic alterations due to administration of cocaine. The goal of the proposed research is to separately measure the base set of fMRI observables - CBF, CBV, BOLD signal, and CMR02 - during a functional response to cocaine in a rat model, and to determine the relationships that couple each quantity to glucose metabolism. The fundamental hypothesis is that cerebral hemodynamic and metabolic alterations to a psychoactive drug are coupled in identifiable ways, and measurements of BOLD signal - a complex combination of these variables which is currently the fMRI tool of choice in humans- can be reliably related to changes in perfusion and glucose metabolism. Measurements will be performed in two rat models: 1) naive rats anesthetized by halothane, a model in which regional increases in glucose metabolism following acute cocaine administration correlate with similar measurements in awake, naive rats, and 2) rats chronically exposed to cocaine, a model which is expected to exhibit altered physiology. These studies seek to validate the physiological basis of a promising new technology for study of psychoactive drug action in brain and to increase our understanding of the neurobiology of cocaine.