The underlying goal of this project is to understand the molecular and synaptic processes that drive the hemodynamic response to a dopaminergic stimulus. This knowledge is crucial to proper interpretation of the changes observed in humans after pharmacologic challenges such as cocaine or amphetamine. First we will investigate the application of high magnetic susceptibility contrast agents to improve the MRI response to dopaminergic stimulation comparing pharmacological MRI (phMRI) measurements of blood oxygenation level dependent (BOLD) contrast or relative cerebral blood volume (rCBV). Then we will test the ability of selective dopamine D1 and D2 antagonists to block the phMRI signal changes induced via dopamine transporter blockers or amphetamine. Concurrently, we will test the hypothesis that hemodynamic changes are linearly proportional to dopamine concentrations by making microdialysis measurements of dopamine concentrations in striatum and frontal cortex. We will develop a quantitative model of CBV changes induced by dopaminergic stimulus combining the microdialysis information and receptor modeling. Then we will perform selective presynaptic dopamine fiber lesions using unilateral injections of 6-hydroxydopamine in the substantial nigra and selective unilateral lesioning of the postsynaptic striatal neurons using quinolinic acid injections. We will perform PET measurements of DAT, and D1 and D2 receptors to determine their correlations with the phMRI. Subsequently, we will examine the role of receptor supersensitivity using the lesion models above to determine the quantitative differences between the two striata after stimulation with apopmorphine or amphetamine, two compounds known to elicit opposite behavioral effects in these lesion models based upon dopamine receptor supersensitivity. These results will be correlated with quantitative PET measurements in the same animal of dopamine receptor binding properties. These studies should lead to a fundamental understanding of the synaptic and molecular underpinnings of behavioral - hemodynamic coupling which is crucial to use sophisticated neuroimaging tools like phMRI as well as fMR1. Ultimately, application of these tools will aid in developing a biological and physiological basis for understanding of human drug abuse.
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