The administration of various doses of the phenylisopropylamine hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) to rats produced dose-related decreases in 1-hr food intake in a food-restricted paradigm and in locomotor activity. DOM also produced dose-related increases in temperature. Pretreatment with propranolol [a beta adrenoceptor antagonist that also has high binding affinity for serotonin (5-HT) 5-HT1A, 5-HT1B and 5-HT2C sites], bemesetron or ondansetron (5-HT3 antagonists) did not attenuate either DOM-induced hypophagia or hyperthermia. In contrast, pretreatment with metergoline (a 5-HT1/5-HT2 antagonist) and ritanserin (a 5-HT2A/5-HT2C antagonist) significantly attenuated both DOM-induced hypophagia and hyperthermia. However, pretreatment with mesulergine (a 5-HT2C/5-HT2A antagonist) significantly attenuated DOM-induced hyperthermia but not hypophagia. On the other hand, spiperone (5-HT1A/5-HT2A/D2 antagonist) pretreatment significantly attenuated DOM-induced hyperthermia but accentuated DOM-induced hypophagia. Daily administration of DOM (1.0 mg kg-1 day-1) produced complete tolerance to its hypophagic effect by day 4 but did not produce cross-tolerance to m-chlorophenylpiperazine-induced hypophagia. In contrast, daily administration of DOM for 7 days did not produce either tolerance to its hyperthermic effect or modify m-chlorophenylpiperazine-induced hyperthermia in rats. These findings suggest that DOM-induced hypophagia and hyperthermia in rats are mediated by stimulation of 5-HT2a receptors.