Relationships between drug-induced changes in tetrahydrobiopterin and biogenic amine concentrations in rat brain

In vitro studies of rat brain tyrosine hydroxylase and tryptophan hydroxylase activities have demonstrated nonlinearities in both time course and substrate velocity curves that were sensitive to small changes in tetrahydrobiopterin (BH4) concentrations when studied within a range speculated to approximate the in vivo condition. High-performance liquid chromatographic determinations of rat striatal BH4 levels reported here are consistent with such a nonlinear relationship of BH4 and brain monoamine synthesis under four in vivo conditions: 1-day s.c. amphetamine infusion, L-tryptophan loads, i.v.t. administration of corticotropin releasing factor and the diurnal rhythms of the dopaminergic nigrostriatal and serotonergic raphe hippocampal systems. Only the results of continuous 10-day amphetamine infusion were consistent with a simple stoichiometric relationship between the (postulated) rate limiting concentrations of BH4 and regional levels of brain monoamines. Although some of the statistically significant changes in regional brain BH4 levels are small, previous reports of the failure of biopterin to change in response to more than 30 other central nervous system drugs, including such stimulants as methylphenidate and cocaine, makes them noteworthy.