EFFECTS OF CENTRAL CHOLINERGIC BLOCKADE ON STRIATAL DOPAMINE RELEASE MEASURED WITH POSITRON EMISSION TOMOGRAPHY IN NORMAL HUMAN-SUBJECTS

Previously we demonstrated that positron emission tomography (PET) can be used to measure changes in the concentrations of synaptic dopamine and acetylcholine. Whether induced directly or indirectly through int eractions with other neurotransmitters, these studies support the use of PET for investigating the functional responsiveness of a specific n eurotransmitter to a pharmacologic challenge. In an extension of these findings to the human brain, PET studies designed to measure the resp onsiveness of striatal dopamine release to central cholinergic blockad e were conducted in normal male volunteers using high-resolution PET a nd [C-11]raclopride, a D2-dopamine receptor antagonist. [C-11]Raclopri de scans were performed prior to and 30 min after systemic administrat ion of the potent muscarinic cholinergic antagonist, scopolamine (0.00 7 mg/kg). After scopolamine administration, [C-11]raclopride binding d ecreased in the striatum (specific binding) but not in the cerebellum (nonspecific binding) resulting in a significant decrease, exceeding t he test/retest variability of this ligand (5%), in the ratio of the di stribution volumes of the striatum to the cerebellum (17%). Furthermor e, scopolamine administration did not alter the systemic rate of [C-11 ]raclopride metabolism or the metabolite-corrected plasma input functi on. These results are consistent not only with the known inhibitory in fluence that acetylcholine exerts on striatal dopamine release but als o with our initial F-18-labeled N-methylspiroperidol and benztropine s tudies. Thus these data support the use of PET for measuring the funct ional responsiveness of an endogenous neurotransmitter to an indirect pharmacologic challenge in the living human brain.