Food restriction and hypoinsulinemia can affect the synthesis, turnover, and receptor function of serotonin (5-HT) in brain. This study explored the effects of food restriction and streptozotocin treatment on behavioral effects related to 5-HT1A (+)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) and 5-HT2A [(±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)] receptor activation. Lower lip retraction and flat body posture (8-OH-DPAT) and head twitching (DOI) were measured in rats during free feeding, food restriction, after treatment with streptozotocin, and finally after insulin replacement. 8-OH-DPAT induced lower lip retraction and flat body posture whereas DOI induced head twitching. One week of food restriction (10 g/day) decreased 8-OH-DPAT-induced lower lip retraction, 8-OH-DPAT-induced flat body posture, and DOI-induced head twitching. Subsequently, 1 week of free access to food restored sensitivity to 8-OH-DPAT and DOI-induced behavioral effects. Finally, 1 week after streptozotocin, 8-OH-DPAT-induced flat body posture and DOI-induced head twitching were markedly reduced whereas 8-OH-DPAT-induced lower lip retraction was unchanged. One week of insulin replacement restored sensitivity to 8-OH-DPAT and DOI-induced behavioral effects. These results show that modest food restriction or experimentally induced diabetes can profoundly affect sensitivity to drugs acting at 5-HT1A or 5-HT2A receptors; these results could be relevant to understanding the comorbidity of depression and diabetes.