This competing renewal seeks to continue funding for our studies to understand the mechanisms behind MRI signal changes associated with dopaminergic drugs. In this application we will seek to determine the components of the signal changes that are related to stimulation of the various dopamine receptor sub-types. In addition, we will correlate these changes with changes that are noted in dopamine release as determined using microdialysis techniques and with quantitative measurements of dopamine receptors using positron emission tomography (PET) and autoradiographic techniques. Further, we will probe the effects that blocking different dopamine receptor sub-types will have on the hemodynamic changes elicited by drugs of abuse such as cocaine and amphetamines. Then we will assay how these receptor sub-types change in two different models of dopaminergic modulation. In the first, we will examine changes that are attendant upon cocaine self-administration. Thus, we will perform longitudinal measurements of changes in dopamine receptor sub- types as a function of cocaine exposure and withdrawal. These changes will be assayed using both real time PCR, PET imaging, MRI and microdialysis. We will also perform companion studies using the 6-OHDA dopamine model to examine the effects of dopaminergic depletion on dopamine receptor subtypes, and their effects on signal changes evoked by drugs such as cocaine and amphetamine. Finally, we will improve both our quantitative ability to acquire the data using higher contrast to noise techniques as well as model the signal changes using dopaminergic release and reuptake curves.
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