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

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.