We scrutinized whether the hyperglycemic status changed the concentration of prototype neuropeptides cyclo(His-Pro) and thyrotropin-releasing hormone (TRH) in the rat brain. Streptozocin-induced hyperglycemia caused a significant increase in cyclo(His-Pro) concentration in the striatum but not in the other brain regions, whereas TRH concentration in any brain region did not differ between control and hyperglycemic groups. Insulin injection normalized blood glucose level and prevented an increase in cyclo(His-Pro) concentration after hyperglycemia. These data indicate that hyperglycemia causes a profound alteration in cyclo(His-Pro) concentration in the rat brain striatum.