EFFECTS OF 6R-L-ERYTHRO-5,6,7,8-TETRAHYDROBIOPTERIN ON THE DOPAMINERGIC AND CHOLINERGIC RECEPTORS AS EVALUATED BY POSITRON EMISSION TOMOGRAPHY IN THE RHESUS-MONKEY

The effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP) on th e central cholinergic and dopaminergic systems in the Rhesus monkey br ain were investigated by positron emission tomography (PET) with the m uscarinic cholinergic receptor ligands (N-[C-11]methyl-benztropine) an d dopaminergic receptor ligands selective for D-1, D-2, and D-3 subtyp es ([C-11]SCH23390, N-[C-11]methyl-spiperone, and (+)[C-11]UH232, resp ectively). None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP used significantly affected the regional cerebral blood flow (rCBF as dete rmined by Raichle's (H2O)-O-15 method), and 10 mg/kg of R-THBP had lit tle effect on the regional cerebral metabolic rate of glucose (rCMRglc ) in the Rhesus monkey brain, as assessed by the graphical [F-18]fluor o-deoxyglucose method. The effect of R-THBP on the muscarinic choliner gic system was dose dependent; while 3 mg/kg of R-THBP did not signifi cantly alter the uptake ratio of N-[C-11]methyl-benztropine in several brain regions to that in the cerebellum, 10 and 30 mg/kg of R-THBP si gnificantly reduced the uptake ratio in the thalamus, as well as in th e frontal and temporal cortices. None of the doses (3, 10, and 30 mg/k g i.v.) of R-THBP tested affected [C-11]SCH23390 (dopamine D-1 recepto r) binding. However, the k3 value for N-[C-11]methyl-spiperone (dopami ne D-2 receptor) binding, which represents the association rate x B-ma x value, was significantly decreased in the striatum. The uptake ratio of (+)[C-11]UH232 (dopamine D-3 receptor) in the striatum to that in the cerebellum was also decreased by administration of R-THBP (3 and 3 0 mg/kg i.v.). These findings suggest that R-THBP acts on dopamine D-2 and D-3 receptors selectively without markedly affecting dopamine D-1 receptor binding. Furthermore, the changes in cholinergic and dopamin e D-2 and D-3 receptors in vivo can not be attributed to a change in r CBF but may depend on the action of R-THBP.