Orexins, also named hypocretins, are newly described neuropeptides, which are produced almost exclusively in neurons of the lateral hypothalamus and have been shown to increase food intake after intracerebroventricular injection. Leptin, the ob-gene product released from white adipocytes, is suspected to reduce food intake mainly by acting on neurons in the arcuate nucleus of the hypothalamus. Application of orexin A activated 85% (66 out of 78) of all neurons of the rat arcuate nucleus investigated electrophysiologically in an in vitro slice preparation, by a direct excitatory postsynaptic effect. Leptin inhibited electrical activity in 10 out of 22 orexin-sensitive neurons in this brain region and excited only 3 neurons. These data give the first indication as to where and how orexin might interact with the leptin-responsive hypothalamic network.