This revision of R01 DA09469-01 has been designed to study the dopamine transporter during withdrawal in patients with cocaine dependence disorders. Relationships between withdrawal symptom severity and regional cerebral transporter dysfunction will be measured with single photon emission computed tomography (SPECT). The patient population will include inpatients who will be participating in a larger investigation of cocaine dependence sponsored by the Addictions Treatment Research Center. The first set of measurements will be required within 48 hours of admission to the program. The scans will then be repeated after 2 and 4 weeks of rehabilitation. A group of experienced clinical investigators will periodically grade symptom severity. Rating scales will be used to relate clinical features of the disorder with regional cerebral transporter concentrations. Differences with matched controls and normal variability will be characterized by studying healthy volunteers twice during a 2-week interval. The repeated measures design will also allow comparisons with patients to determine whether any transporter abnormalities that are found resolve with abstinence. Regional changes in transporter concentrations will be related to the clinical course during the inpatient and partial hospitalization phases of rehabilitation and to relapse rates during 12 months of followup by the Treatment Research Center faculty. Regional cerebral transporter concentrations will be measured non-invasively with N-(3-iodopropen-2-yl)-2-beta-carbomethoxy-3-beta-(4-chlorophenyl)tropane (IPT). IPT is a selective dopamine reuptake site inhibitor with a dissociation constant (Kd) for the transporter of 0.3 nM. Studies of healthy human volunteers have demonstrated that IPT has several very advantageous imaging characteristics that may eventually make it one of the radiopharmaceuticals of choice for measuring transporter function in both clinical and research settings. The uptake in the brain is rapid. Its basal ganglia to background ratio exceeds 30 to 1 at 3 hours after administration in some young adults. Its relatively fast elimination from regions of non-specific binding appears to facilitate its kinetic modeling. Relatively high count rates tend to improve the statistics that can be obtained during dynamic studies in relatively small regions by co-registering the images with MRI scans. The progress that has been made since the initial application was submitted has been very encouraging. The dosimetry studies were performed. The findings were favorable and are now in press. Measurements of test-retest precision in controls have shown that the kinetic measurements are reliable and will allow sequential images in the same subjects to be compared directly with each other. Absolute quantification remains a goal, but encouraging studies of accuracy have now been completed with phantoms and nonhuman primates which suggest that the measurements can be calibrated. The results in humans have produced some discrepancies between the 5 different models we have applied. However, the amenability of the data to analyses with multiple models increases the likelihood that studying this patient population with IPT will increase the understanding of normal transporter function and its association with the symptoms of cocaine withdrawal.
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