In order to assess the role of the serotonergic system in the development of tolerance to ethanol in the mouse, serotonin neurons in the CNS were lesioned with an intracerebroventricular injection of the neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). Mice injected with 5,7-DHT responded to an acute dose of ethanol with a longer sleep time and greater fall in body temperature than CSF-treated mice. The increased response to acute administration of ethanol was accompanied by higher circulating levels of ethanol in mice pretreated with 5,7-DHT. When mice were fed an ethanol-containing liquid diet for five days, a higher mortality rate was observed in the 5,7-DHT group compared to the CSF pretreated group of mice. When the groups of mice were tested for tolerance 24 hours after withdrawal, the 5,7-DHT group was less tolerant than the CSF group. Therefore, damage to the serotonin neurons results in altered ethanol disposition, altered initial sensitivity to ethanol, and an inhibition in the development of tolerance in the mouse.