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Use of Positron Emission Tomography to Study the Dynamics of Psychostimulant-Induced Dopamine Release

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Abstract

Microdialysis studies have shown that psychostimulants act through a common neurochemical mechanism of elevating synaptic dopamine content in the mesocorticolimbic dopaminergic system. However, little information is available regarding the dynamics of the interaction between the elevated synaptic dopamine levels induced by a psychostimulant and postsynaptic dopamine receptors. The goal of the current investigation was to determine if positron emission tomography (PET) studies using the dopamine D2-selective radioligand [18F]4′-fluoroclebopride ([18F]FCP) could be used to measure synaptic dopamine levels. Rhesus monkeys were used because our previous studies revealed that [18F]FCP has a low test/retest variability in this species. Under control conditions, [18F]FCP had a high uptake and slow rate of washout from the basal ganglia, a region of brain that expresses a high density of D2 receptors, reaching kinetic equilibrium at ∼40 min. Challenge studies, each separated by at least 1 month, were conducted by administering an intravenous dose of (−)cocaine, d-amphetamine, methylphenidate, or d-methamphetamine (1.0 mg/kg) at 40 min post-IV injection of a no-carrier-added dose of [18F]FCP. In each case, the psychostimulant caused an increase in the rate of washout of [18F]FCP from the basal ganglia. Methamphetamine and amphetamine had more pronounced effects on the washout kinetics of [18F]FCP relative to cocaine and methylphenidate, a result that is consistent with the ability of each drug to elevate synaptic dopamine levels. Our results indicate that challenge studies with [18F]FCP may be a useful technique for studying the dynamics of the interaction between psychostimulant-induced increases in synaptic dopamine and postsynaptic D2 receptors.

Section snippets

Radiosynthesis

The synthesis of [18F]FCP was accomplished via N-alkylation of the corresponding des-benzyl precursor with [18F]4-fluorobenzyliodide ([18F]FBI), as described previously 24, 26. The synthesis time was ∼120 min, and the overall yield ranged from 10 to 56%; the specific activity of the final product ranged from 1000 to 5000 mCi/μmol.

PET Data Acquisition in Rhesus Monkeys

Images were acquired on a Siemens CTI 951/31 PET Scanner. The in-plane resolution of the scanner was measured to be 6.0–6.5 mm full width at half maximum (FWHM) in the

Results

The results of a PET imaging study, coregistered with an MRI image of the test subject, are shown in Fig. 2. Note the high uptake of [18F]FCP in the basal ganglia, a brain region expressing a high density of dopamine D2 receptors. Representative tissue–time activity curves from a dynamic imaging study are shown in Fig. 3. There is a high accumulation of radiotracer in the BG (Fig. 3, open triangles) and a low uptake and rapid rate of washout of radioactivity from the Cb, a reference region

Discussion

It is now generally accepted that the positive reinforcing effects of psychostimulants are mediated, in large part, through the elevation of synaptic dopamine concentrations in the mesocorticolimbic dopaminergic system. Although the principal site of action for many psychostimulants resides on molecular targets located on the presynaptic dopaminergic terminal, the reinforcing effects of psychostimulants are mediated, in large part, through the interaction of the elevated synaptic dopamine with

Acknowledgements

We thank Mr. Brian Whirrett, Ms. Virginia Kirby, Mr. Clifford Hubbard, Ms. Debbie Gibbons, Ms. Holly Choate, and Ms. Joanne Dow for their excellent technical assistance. This research was funded by grant NS 31907 awarded by the National Institutes of Health.

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