Tryptophan Loading: Consequent Effects on the Synthesis of Kynurenine and 5‐hydroxyindoles in Rat Brain

Tryptophan loading of rats resulted in a continuous non‐linear uptake of l‐tryptophan from plasma into the brain. The optimum tryptophan load for increasing cerebral 5‐hydroxytryptamine (5‐HT) level was 25 mg/kg. Above this, there was a gradual decrease both in the levels and synthesis of 5‐HT and 5‐hydroxyindoleacetic acid (5‐HIAA) as assessed from simultaneous intraperitoneal or intraventricular injections of l[14C]tryptophan. A 5–10 fold increase in cerebral tryptophan produced a limited stimulation of 5‐HT synthesis. When the cerebral tryptophan level reached 1 ± 10‐4, substrate inhibition in vivo of the tryptophan monooxygenase (tryptophan‐5‐hydroxylase) but not of the indoleamine‐2,3‐dioxygenase occurred. Cerebral synthesis of kynurenine increased linearly with increasing tryptophan load. At a plasma ratio of 50:1 tryptophan to kynurenine, tryptophan loading interfered with the entry of peripheral kynurenine. Tryptophan loading also increased the efflux of 5‐hydroxyindoles from the brain. One hour after intraperitoneal injection of l‐kynurenine sulfate (5 mg/kg) into rats, there was a shift in the plasma ratio of l‐tryptophan to l‐kynurenine to 4:1. In these rats, a 20% reduction of cerebral tryptophan was noted.