Hypothalamic neuronal histamine has been shown to regulate feeding behavior and energy metabolism as a target of leptin action in the brain. The present study aimed to examine the involvement of L-histidine, a precursor of neuronal histamine, in the regulation of feeding behavior in rats. Intraperitoneal (ip) injection of L-histidine at doses of 0.35 and 0.70 mmol/kg body weight significantly decreased the 24-hr cumulative food and water intakes compared to phosphate buffered saline injected controls (P < 0.05 for each). This suppression of feeding was mimicked dose-dependently by intracerebroventricular infusion of histidine at doses of 0.5, 1.0, and 2.0 micromol/rat (P < 0.05 for each). Pretreatment of the rats with an ip bolus injection of alpha-fluoromethylhistidine, a suicide inhibitor of a histidine decarboxylase (HDC), at a dosage of 224 micromol/kg blocked the conversion of histidine into histamine and attenuated the suppressive effect of histidine on food intake from 64.2% to 88.1% of the controls (P < 0.05). Administration of 0.35 mmol/kg histidine ip increased the concentration of hypothalamic neuronal histamine compared with the controls (P < 0.05). HDC activity was increased simultaneously by histidine administration compared with the controls (P < 0.05). The present findings indicate that L-histidine suppresses food intake through its conversion into histamine in the hypothalamus.