Effects of intraventricular methotrexate on cerebrospinal fluid monoamine metabolites in rhesus monkeys

Previous work suggested that methotrexate (MTX) may cause encephalopathy by inhibiting biosynthetic pathways for dopamine and serotonin in the brain. We examined this issue by measuring the neurotransmitter metabolites homovanillic acid and 5-hydroxyindoleacetic acid in the lumbar CSF of rhesus monkeys receiving continuous intracerebroventricular infusions of MTX or dichloromethotrexate. Infusion of the lowest dose (0.05 mg/day) produced a large (300%) rise in homovanillic acid levels and a modest elevation in 5-hydroxy-indoleacetic acid. During higher dose infusion, which was associated with clinical encephalopathy, the biogenic amine metabolites fell from their previous elevated levels. In one encephalopathic monkey, an injection of 1 mg of leucovorin produced a marked elevation in CSF monoamine metabolites within 1 hour and rapid clinical recovery. In contrast, leucovorin produced no change in monoamine metabolites in control animals. The data suggest that MTX may block egress of monoamine metabolites from CSF at the lower doses and suppress neurotransmitter turnover at toxic doses which cause encephalopathy. Serial measurements of CSF monoamine metabolites deserve further investigation as biochemical markers for toxic effects of MTX on neuronal metabolism in the CNS.