PRESYNAPTIC AND POSTSYNAPTIC ACTIONS AND MODULATION OF NEUROENDOCRINENEURONS BY A NEW HYPOTHALAMIC PEPTIDE, HYPOCRETIN OREXIN/

A new orexigenic peptide called hypocretin (orexin) has recently been described in neurons of the lateral hypothalamus and perifornical area . The medial and lateral hypothalamus have been loosely called satiety and feeding centers of the brain, respectively. Approximately one-thi rd of all medial and lateral hypothalamic neurons tested, but not hipp ocampal neurons, show a striking nanomolar sensitivity to hypocretin. As studied with calcium digital imaging with fura-2, hypocretin raises cy toplasmic calcium via a mechanism based on G-protein enhancement o f calcium influx through plasma membrane channels. The peptide has a p otent effect at both presynaptic and postsynaptic receptors. Most syna ptic activity in hypothalamic circuits is attributable to axonal relea se of GABA or glutamate, With whole-cell patch-clamp recording, we sho w that hypocretin, acting directly at axon terminals, can increase the release of each of these amino acid transmitters. Two hypocretin pept ides, hypocretin-1 and hypocretin-2, are coded by a single gene; neuro ns that respond to one peptide also respond to the other, In addition to its effect on feeding, we find that this peptide also regulates the synaptic activity of physiologically identified neuroendocrine neuron s studied in hypothalamic slices containing the arcuate nucleus, sugge sting a second function of hypocretin in hormone regulation. The wides pread distribution of hypocretin axons, coupled with the strong respon se to the peptide at both presynaptic and postsynaptic sites, suggests that the peptide probably modulates a variety of hypothalamic regulat ory systems and could regulate the axonal input to these regions presy naptically.