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Bradberry & Colleagues

Imaging dopamine transmission in the frontal cortex: a simultaneous microdialysis and [(11)C]FLB 457 PET study

Narendran R, Jedema HP, Lopresti BJ, Mason NS, Gurnsey K, Ruszkiewicz J, Chen CM, Deuitch L, Frankle WG, Bradberry CW.

Abnormal dopamine levels in the brain’s prefrontal cortex have a negative effect on neurocognitive functions, such as memory, attention and problem-solving. Altered levels of the neurotransmitter in this brain region have also been implicated in neurological and psychiatric disorders, including schizophrenia and Parkinson’s disease. Having a method of characterizing prefrontal dopamine release in patients with neuropsychiatric disorders could vastly improve current methods of diagnosis and treatment.

In a recent human PET (positron emission tomography) study, Drs. Bradberry and Narendran, and colleagues at the University of Pittsburgh, used a psychostimulant drug, amphetamine, to induce dopamine release in the prefrontal cortex, and observed the effects that this release had had on the binding of a trace amount of a radioactive ligand ([11C]FLB 457). They demonstrated that a reduction in [11C]FLB 457, which competes with dopamine for the same receptor, indicates dopamine release.

In order to validate this model for its application in clinical studies, it was necessary to show that the observed ligand binding was a result of actual changes in the brain’s extracellular dopamine. To do this, changes the neurotransmitter were measured using microdialysis in a non-human primate study. For this study, three different doses of amphetamine were administered in each research case, then dopamine release and [11C]FLB 457 displacement were monitored. A linear relationship was found to exist between the amphetamine-induced peaks in dopamine and changes in the ligand’s binding potential ([11C]FLB 457 BPND).

The use of this [11C]FLB 457-amphetamine imaging paradigm in humans should allow for characterization of prefrontal cortical dopamine release in neuropsychiatric disorders such as schizophrenia and addiction.

Contributors:
Hank Jedema, PhD, K Gurnsey, J Ruszkiewicz, CM Chen, L Deuitch, William G. Frankle, MD, Charles Bradberry, PhD   (Department of Psychiatry and Center for Neuroscience, University of Pittsburgh)
Rajesh Narendran, MD, Brian Lopresti, BS, Neale Mason, PhD (Department of Radiology, University of Pittsburgh)

The results of this investigation were published in the February 2013 issue of the Molecular Psychiatry. Click here for a link to the abstract.