Numerous peripheral and hypothalamic peptides control food intake. Among these signals are orexin, an orexigenic molecule released into the olfactory bulb by centrifugal hypothalamic fibres and leptin, an anorexigenic molecule that is released peripherally and can pass through the blood-brain barrier. In the present study, we injected either orexin or leptin, intracerebroventricularly, and their effect on olfactory performance was evaluated in two groups of rats, using a behavioral paradigm based on conditioned olfactory aversion. Rats were made aversive to water odorized with isoamyl acetate (ISO) at 10(-5) (1microl in 100ml of water). One group was injected with orexin versus saline and the other with leptin versus saline. They were then presented with different concentrations (lower than 10(-5)) of ISO-odorized water to compare their ability to avoid the ISO-drink. Orexin decreased ISO-drink consumption, showing increased avoidance of the ISO concentrations tested which ranged from 10(-9) to 10(-7). Conversely, the administration of leptin resulted in a dose dependant increase in the odorized-drink consumption for ISO 10(-10). Orexin therefore increases and leptin decreases olfactory sensitivity. Orexin and leptin modulate the olfactory performance in a similar way as do physiological induced fasting and satiation and appear to be important factors in the interdependency of olfaction and food intake.