Studies of radiation effects on performance are often complicated by concurrent radiation-induced decreases in feeding behavior (i.e., "anorexia"). To evaluate the pharmacological specificity of these decreases in food intake, the interactions of radiation with three prototypical drugs were studied. Single daily i.p. administration of a dose of chlordiazepoxide, ondansetron or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was given to groups of rats for 5 days after either a single nonlethal 4.5-Gy dose of ionizing radiation (bremsstrahlung or gamma rays) or a sham exposure. The food intake for each group was measured 60 min and 24 hr after food presentation. Radiation alone significantly decreased food intake during the 60-min test on each treatment day and for the 5-day period when data were averaged. Chlordiazepoxide (1.8-18 mg/kg) and 8-OH-DPAT (0.1-1 mg/kg) produced significant dose-dependent increases in food intake during the 60-min test in both irradiated and sham-irradiated groups, whereas ondansetron (0.1-1 mg/kg) did not alter food intake at any dose tested. The dose effects at 60 min were significant on each treatment day for chlordiazepoxide, on 4 of 5 days for 8-OH-DPAT and for both drugs when data for all 5 days were combined. In no case, however, was a significant interaction obtained for radiation and any dose of the three drugs. After 24 hr, decreases in intake were obtained in a few subjects in 3 of 12 total radiation groups. These results suggest that radiation-induced decreases in food intake do not result from damage to the mechanisms by which chlordiazepoxide and 8-OH-DPAT increase food intake and that hyperphagic agents from these two different classes may have therapeutic value for attenuating radiation-induced anorexia.