AMPHETAMINE EFFECTS ON DOPAMINE RELEASE AND SYNTHESIS RATE STUDIED INTHE RHESUS-MONKEY BRAIN BY POSITRON EMISSION TOMOGRAPHY

Positron emission tomography (PET) was used in a multitracer protocol to evaluate D-amphetamine induced effects on dopamine biosynthesis rat e and release in propofol anesthetized Rhesus monkeys. L-[beta-C-11]DO PA was used as biochemical probe to study the brain dopamine biosynthe sis rate whilst dopamine release was followed by the binding displacem ent of the [C-11]-radiolabelled dopamine receptor antagonists, raclopr ide and N-methylspiperone. Studies were performed with either a consta nt rate intravenous infusion of D-amphetamine aiming at plasma concent rations of 0.2 to 25 ng/ml or with intravenous bolus doses of 0.1 and 0.4 mg/kg. Decreased binding of the dopamine receptor antagonists was measured in both modes of D-amphetamine administration but notably [C- 11]N-methylspiperone was less able to sense D-amphetamine induced rele ase of dopamine. At plasma concentrations aimed above 1 ng/ml a levell ing off of the binding of [C-11]raclopride at 68 +/- 8.1% of the basel ine value indicated that displacement was only possible from a fractio n of the binding sites. Amphetamine was observed to increase the rate constant for L-[beta-C-11]DOPA utilization in the brain. This was most likely due to an acutely induced subsensitivity of presynaptic dopami ne receptors. L-[(beta-C-11]DOPA and [C-11]raclopride were found suita ble to indicate changes in dopamine synthesis rate and release respect ively using PET and can be used to mirror drug-induced changes of brai n dopaminergic function.