The influence of D-amphetamine on rat brain striatal reduced biopterin concentration

Rat brain striatal reduced biopterin (BH4) levels vary diurnally by 2-fold, oscillating around a concentration of 3 micrometer. D-Amphetamine consistently induced a decrease in BH4 levels that did not exceed 25 to 30% with increasing doses; recovery of control levels required several hours. A large number of other psychotropic drugs, including other stimulants and phenylethylamine congeners, failed to induce a similar change. The amphetamine effect was blocked by methylphenidate and reserpine. The prolonged time for BH4 recovery could be explained by an amphetamine-induced functional uncoupling of quinonoid dihydropteridine reductase from striatal tyrosine hydroxylase as reported for various cofactor analogs, leading to spontaneous isomerization of the partially reduced pterin to its nonquinonoid form, which is not a substrate for the BH4 regenerating enzyme. If relevant to dopamine biosynthesis, such an uncoupling phenomenon might account for a unique neuropharmacology of the postamphetamine state.