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 the central cholinergic and dopaminergic systems in the Rhesus monkey brain were investigated by positron emission tomography (PET) with the muscarinic cholinergic receptor ligands (N-[C]methyl-benztropine) and dopaminergic receptor ligands selective for D D, and D subtypes ([C]SCH23390, N-[C]methyl-spiperone, and (+)[C]UH232, respectively). 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 determined by Raichle's HO method), and 10 mg/kg of R-THBP had little effect on the regional cerebral metabolic rate of glucose (rCMRglc) in the Rhesus monkey brain, as assessed by the graphical [F]fluoro-deoxyglucose method. The effect of R-THBP on the muscarinic cholinergic system was dose dependent; while 3 mg/kg of R-THBP did not significantly alter the uptake ratio of N-[C]methyl-benztropine in several brain regions to that in the cerebellum, 10 and 30 mg/kg of R-THBP significantly reduced the uptake ratio in the thalamus, as well as in the frontal and temporal cortices. None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP tested affected [C]SCH23390 (dopamine D receptor) binding. However, the k3 value for N-[C]methyl-spiperone (dopamine D receptor) binding, which represents the association rate × B value, was significantly decreased in the striatum. The uptake ratio of (+)[C]UH232 (dopamine D receptor) in the striatum to that in the cerebellum was also decreased by administration of R-THBP (3 and 30 mg/kg i.v.). These findings suggest that R-THBP acts on dopamine D and D receptors selectively without markedly affecting dopamine D receptor binding. Furthermore, the changes in cholinergic and dopamine D and D receptors in vivo can not be attributed to a change in rCBF but may depend on the action of R-THBP. [ABSTRACT FROM AUTHOR]