Ketamine inhibits serotonin synthesis and metabolism in vivo.

Ketamine (160 mg/kg, i.p.) was found to reduce the accumulation of 5-hydroxytryptophan (5-HTP) in whole brain following inhibition of L-aromatic amino acid decarboxylase with 50 mg/kg of 3-hydroxybenzylhydrazine (NSD-1015). Smaller doses of ketamine did not affect whole brain 5-HTP accumulation. However in regional studies, 80 mg/kg of ketamine significantly reduced 5-HTP accumulation in the spinal cord and the midbrain-thalamus. A dose of 160 mg/kg ketamine also reduced 5-HTP accumulation in the spinal cord and midbrain-thalamus and in the medulla-pons, striatum and cortex as well. No significant changes in 5-HTP accumulation were observed in the hypothalamus or hippocampus. Ketamine (160 mg/kg) also reduced whole brain 5-hydroxyindoleacetic acid (5-HIAA) levels and slightly elevated whole brain 5-hydroxytryptamine (5-HT) levels. Smaller doses did not affect either 5-HIAA or 5-HT levels. Ketamine did not affect whole brain tryptophan levels nor did it inhibit [3H]tryptophan uptake or conversion to [3H]5-HT in vitro. These data demonstrate that ketamine reduced both 5-HT synthesis and metabolism in vivo. Since ketamine did not affect brain tryptophan levels nor did it inhibit 5-HT in vitro, the reduction of 5-HT turnover following ketamine administration appears to be a neuronal, adaptive phenomenon possibly occurring in response to a blockade of 5-HT uptake by ketamine.