USE OF POSITRON EMISSION TOMOGRAPHY TO STUDY THE DYNAMICS OF PSYCHOSTIMULANT-INDUCED DOPAMINE RELEASE

Microdialysis studies have shown that psychostimulants act through a c ommon neurochemical mechanism of elevating synaptic dopamine content i n the mesocorticolimbic dopaminergic system. However, little informati on is available regarding the dynamics of the interaction between the elevated synaptic dopamine levels induced by a psychostimulant and pos tsynaptic dopamine receptors. The goal of the current investigation wa s to determine if positron emission tomography (PET) studies using the dopamine D-2-selective radioligand [F-18]4'-fluoroclebopride ([F-18]F CP) could be used to measure synaptic dopamine levels. Rhesus monkeys were used because our previous studies revealed that [F-18]FCP has a l ow test/retest variability in this species. Under control conditions, [F-18]FCP had a high uptake and slow rate of washout from the basal ga nglia, a region of brain that expresses a high density of D-2 receptor s, reaching kinetic equilibrium at similar to 40 min. Challenge studie s, 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-car rier-added dose of [F-18]FCP. In each case, the psychostimulant caused an increase in the rate of washout of [F-18]FCP from the basal gangli a. Methamphetamine and amphetamine had more pronounced effects on the washout kinetics of [F-18]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 [F-18]FCP may be a useful technique for studying the dynamics of the interaction between psychostimulant-induced increases in synaptic dopamine and postsynaptic D-2 receptors. (C) 1997 Elsevier Science Inc .