Surprising signs of reduced activation and food intake after intranasal application of orexin A (hypocretin-1) in humans

Orexin A (hypocretin-1) induces food intake in animal experiments which may be secondary to its enhancing effects on activation. In an exploratory study we assessed effects of orexin A on EEG, food intake and feelings of activation in humans. Direct current (DC)-potentials were recorded from the scalp of 15 food-deprived subjects who were intranasally administered either 100 nmol of orexin A or placebo prior to recordings. During recordings, subjects ingested 400ml of liquid food in both conditions. Before and after sessions, subjects rated feelings of tiredness and filled in an adjective check list assessing mood and activation. They were allowed to eat rolls ad libitum afterwards. In the placebo condition, food intake was as expected followed by a widespread positive DC-potential shift within 3min after intake of liquid food. Orexin A did not significantly change the observed DC-potential pattern but had unexpected effects on behavioral measures. In the placebo condition, rated tiredness declined during the session (p<0.01), whereas in the orexin condition it remained stable (p>0.7), slightly exceeding placebo values at the end of the test (p=0.12). There also was a slight trend towards greater tiredness according to the adjective check list after orexin treatment (p=0.11). Also, subjects in the orexin condition tended to eat less after recordings (p<0.08). Data indicate that contrary to expectations, a small dose of intranasal orexin A appears to increase tiredness and reduce food intake in humans, pointing to a dose-dependent impact of the substance on hypothalamic networks in the CNS. Also, its actions might vary depending on the sites it accesses after intranasal application.