We have measured the concentrations of substance P, somatostatin, homovanillic acid (HVA), vanillyl mandelic acid (VMA) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) of six patients suffering from narcolepsy and 12 age- and gender-matched controls using high pressure liquid chromatography (HPLC) and radioimmunoassay (RIA). Substance P and somatostatin were significantly decreased in our patients compared to controls (36.9 +/- 9.1 fmol/ml versus 52.5 +/- 9.9 fmol/ml, P < 0.05 and 30.3 +/- 7.8 fmol/ml versus 43.9 +/- 9.8 fmol/ml, P < 0.05, respectively). 5-HIAA (P < 0.05) and VMA (P < 0.05) were also significantly decreased. HVA was significantly increased (P < 0.01). The CSF concentrations of substance P and somatostatin correlated with the clinical parameters duration of disease (r = -0.68, P < 0.05 and r = -0.72, P < 0.05, respectively) and severity of cataplectic symptoms (r = -0.71, P < 0.05 and r = -0.78, P < 0.01). In addition, substance P correlated with the intensity of sleepiness and the frequency of day-sleep attacks (r = -0.69, P < 0.05 and r = -0.68, P < 0.05, respectively). Substance P affects the amount of dopamine release in the nigra-striatal region, and decreased amounts could contribute to the pathogenesis of narcolepsy. Reduced levels of substance P, which affects serotonin release, may be responsible for diminished release of serotonin which in turn could affect sleep cycles. Because somatostatin affects motor behavior through dopaminergic mechanisms and since the levels of somatostatin correlate with the intensity of cataplectic symptoms, we speculate that an interaction between somatostatin and dopaminergic neurons plays a role in the pathogenesis of narcolepsy.