Cyclo(His-Pro) potentiates the reduction of food intake induced by amphetamine, fenfluramine, or serotonin

Electrophysiological and pharmacological evidence suggests that cyclo(His-Pro) (cHP) could reduce food intake by modulating the actions of relevant neurotransmitters. We tested this hypothesis by giving rats a combination of cHP or its analogs centrally and an anorectic, amphetamine or fenfluramine, systemically. Compared to saline control, cHP at doses too low to affect food intake by itself significantly potentiated the reduction of food intake by amphetamine. This potentiation is thought to be due to cHP modulation of norepinephrine (NE) action, because at the low dose used amphetamine acts mainly through NE to inhibit food intake. The modulation has specific requirements for cHP structure, since it was mimicked by one but not two other analogs tested. The anorectic effect of fenfluramine was also potentiated and prolonged by cHP at a dose not effective by itself. Since fenfluramine is known to act by increasing brain serotonin (5-HT), the potentiation was apparently a result of an interaction between cHP and 5-HT effects. To examine this interaction more directly, we administered both cHP and 5-HT centrally. Again, cHP potentiated the reduction of food intake caused by 5-HT. Thus the neuromodulation of feeding-relevant neurotransmitter effects, following NE and 5-HT, is probably a mechanism by which cHP reduces food intake.