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 study the effects of blockers of the dopamine transporter (DAT) (such as cocaine or amphetamine) on the regional distribution of hemodynamic responses in rat brains using 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. These experiments will be followed by study of the hemodynamic consequences of the interactions between dopamine receptors and adenosine receptors by selective antagonism of the adenosine system in combination with stimulus delivered using DAT blockers. Concurrently, we will test the hypothesis that hemodynamic changes are proportional to dopamine concentrations by making microdialysis measurements of dopamine concentrations in striatum and frontal cortex. Then we will preform selective pre-synaptic dopamine fiber lesions using unilateral injections of 6-hydroxydopamine in the substantia nigra, and selective unilateral lesioning of the post-synaptic striatal neurons using quinolinic acid injections. Then we will perform rCBV measurements in these animals After stimulus using DAT blockers to test whether the origins of the phMRI signals are pre-or post-synaptic. We will also perform correlative positron emission tomography (PET) measurements of DAT, and D1 and D2 receptors to determine their correlations with the phMRI. Then, 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 apomorphine 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 animals of dopamine receptor binding properties. Lastly, these studies will be followed by quantitative PET measurements in rats who chronically self administer cocaine to determine what changes in dopamine receptor binding properties accompany chronic cocaine administration. These studies should lead to a fundamental understanding of the synaptic and molecular underpinnings of behavioral-metabolic coupling which is crucial to developing a biological basis for understanding of human drug abuse.
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