Problem: Functional magnetic resonance imaging (fMRI) is being increasingly used to study the effects of cocaine and other drugs on brain function. However, little is known about how the time course of regional uptake and clearance of cocaine in the brain relates to regional dynamic changes in fMRI signals. Here we propose a novel, cutting-edge imaging approach using simultaneous positron emission tomography (PET) and fMRI to capture both the kinetics of cocaine and the functional hemodynamic response to it in the same imaging session. Purpose: The overall goal of this proposal is to optimize the spatial and temporal resolution of the PET/MRI instrument developed in our laboratory to study the pharmacokinetics of cocaine and the pharmacodynamic effects of cocaine on BOLD responses in the brain, simultaneously with PET and fMRI. Methods: A high-performance gradient coil insert will be customized to fit a miniaturized, MRIcompatible PET camera. MRI pulse sequence parameters will be optimized to maximize the MRI acquisition rate and minimize the interference of MRI gradient pulses on PET acquisition. [11C]Cocaine will be used to monitor the pharmacokinetics of cocaine in the rat brain and determine how the rate of drug uptake and clearance alters the fMRI signal. Hypothesis: (1) The MRI-compatible PET instrument will tolerate ultra-fast MRI gradient pulses; (2) Only during the brief rise time of gradient pulses MRI will interfere PET acquisition; and (3) the fMRI signal will only be altered by the pharmacologically active dose of [11C]cocaine and will vary as a function of the rate of drug uptake and clearance. Outcomes: Our dual-modality approach will allow simultaneous mapping of labeled drugs and other biochemical markers together with the hemodynamic response. The proposed technology capitalizes on the unique ability of PET to map the moment-by-moment changes of drug concentration and the ability of fMRI to capture hemodynamic responses with unparalleled temporal and spatial resolution. Thus the proposed PET/fMRI multimodality approach represents a quantum leap bridging drug pharmacokinetics and its affects on brain activity as measured by fMRI-activation through the ability to make both of these measurements in the same animal simultaneously. Benefits: This new technology will provide a novel perspective on how drug actions in the brain translate into changes in regional brain activity. Knowledge from these studies will bridge the existing gap between PET findings of cocaine pharmacokinetics and the observed vascular fMRI responses. This will lay the groundwork for future studies in humans to pinpoint the mechanisms underlying the vascular and behavioral effects of cocaine. ? ? ?
