Re-evaluation of histidyl-proline diketopiperazine [cyclo(His-Pro)] effects on food intake in the rat.

Histidyl-proline diketopiperazine [cyclo(His-Pro)], a metabolite of thyrotropin releasing hormone (TRH), has been reported to decrease food intake of rats in a variety of feeding models following intracerebroventricular (ICV) injection. We have re-evaluated the anorectic effects of cyclo(His-Pro) on food deprivation-induced and spontaneous feeding. When injected ICV at the end of the light period into ad lib fed rats, neither the naturally occurring cyclo(L-His-L-Pro) isomer (14 to 1000 nmole/rat) nor any of the four cyclo(D,L-His-D,L-Pro) stereoisomers (100 nmole/rat) significantly suppressed food intake at any hour for up to 12- or 24-hr post-injection. Bombesin (0.6 nmole/rat ICV) decreased food intake in the same model by up to 86% with anorexia still apparent 15-hr post-injection (71%, p less than 0.001). In two food deprivation-induced feeding models, cyclo(L-His-L-Pro) (100 and 1000 nmole/rat ICV) did not cause anorexia while TRH (10 and 1000 nmole/rat ICV) maximally suppressed food intake by 74% (p less than 0.02) and 50% (p less than 0.01). Occasional transient increases of food consumption were observed in cyclo(His-Pro)-treated rats during both spontaneous and induced feeding. Cyclo(L-His-L-Pro) was also without effect on food intake when intraperitoneally administered at 12.5 and 30 mumole/kg to schedule fed rats. TRH at 30 mumole/kg IP transiently suppressed food intake of schedule fed rats (p less than 0.005). These findings indicate that cyclo(His-Pro) does not exhibit anorectic activity in the rat and cast doubt on the concept that TRH-induced anorexia results from conversion of TRH to an active cyclo(His-Pro) metabolite.