Presynaptic and Postsynaptic Actions and Modulation of Neuroendocrine Neurons by a New Hypothalamic Peptide, Hypocretin/Orexin

Abstract

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-third of all medial and lateral hypothalamic neurons tested, but not hippocampal neurons, show a striking nanomolar sensitivity to hypocretin. As studied with calcium digital imaging with fura-2, hypocretin raises cytoplasmic calcium via a mechanism based on G-protein enhancement of calcium influx through plasma membrane channels. The peptide has a potent effect at both presynaptic and postsynaptic receptors. Most synaptic activity in hypothalamic circuits is attributable to axonal release of GABA or glutamate. With whole-cell patch-clamp recording, we show that hypocretin, acting directly at axon terminals, can increase the release of each of these amino acid transmitters. Two hypocretin peptides, hypocretin-1 and hypocretin-2, are coded by a single gene; neurons 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 neurons studied in hypothalamic slices containing the arcuate nucleus, suggesting a second function of hypocretin in hormone regulation. The widespread distribution of hypocretin axons, coupled with the strong response to the peptide at both presynaptic and postsynaptic sites, suggests that the peptide probably modulates a variety of hypothalamic regulatory systems and could regulate the axonal input to these regions presynaptically.

Reciprocal synaptic relationships between orexin- and melanin-concentrating hormone-containing neurons in the rat lateral hypothalamus: a novel circuit implicated in feeding regulation

“…As more synapses were made by ORX-LI axon terminals on MCH-LI neurons than vice versa, this may reflect the main synaptic direction with synapses from MCH-LI axon terminals to ORX-LI neurons representing a feedback system. Given that the synapses made by ORX-LI axon terminals have usually been identified as excitatory, 23,50 similar to the synapses made by orexinergic axon terminals on neuropeptide Y 21 and noradrenalin 22 containing neurons, the synapses made by ORX-LI axon terminals on MCH-LI neurons found in the present study may also be excitatory. Unfortunately, as we do not know whether the synapses made by the MCH-LI axon terminals are excitatory or inhibitory, the physiological consequences of the feedback from MCH-LI axon terminals to ORX-LI neurons is still to be elucidated.…”

Cardiovascular effects of hypocretin-1 in nucleus of the solitary tract

“…Finally, microinjection of Hcrt-1 into the NTS significantly potentiated the reflex bradycardia to activation of arterial baroreceptors as a result of increasing MAP by systemic injections of phenylephrine (2-4 g/kg). These results suggest that Hcrt-1 in the NTS activates neuronal circuits that increases vagal activity to the heart, inhibits sympathetic activity to the heart and vasculature, and alters the excitability of NTS neuronal circuits that reflexly control the circulation.orexin-A; blood pressure; baroreceptor reflex; brain stem; ingestive behavior HYPOCRETIN (Hcrt) neuropeptides have been recently shown to be almost exclusively expressed within neurons of the lateral and perifornical hypothalamic areas (30,33,35,47,49). These peptides, Hcrt-1, a 33 amino-acid peptide with an NH 2 -terminal pyrogutalmyl residue, and Hcrt-2, a 28 amino acid peptide with a COOH-terminal amide (35), are de-…”

“…orexin-A; blood pressure; baroreceptor reflex; brain stem; ingestive behavior HYPOCRETIN (Hcrt) neuropeptides have been recently shown to be almost exclusively expressed within neurons of the lateral and perifornical hypothalamic areas (30,33,35,47,49). These peptides, Hcrt-1, a 33 amino-acid peptide with an NH 2 -terminal pyrogutalmyl residue, and Hcrt-2, a 28 amino acid peptide with a COOH-terminal amide (35), are de-…”

“…Hcrt-2 has been reported to have 46% similarity with Hcrt-1 (35), and both peptides bind and activate G protein-coupled receptors (11,35). Although both Hcrt-1 and -2 have been shown to have similar physiological effects when administered centrally, Hcrt-1 appears to exert a more potent effect on most of these physiological variables (10,12,33,42,47). Hcrt-1 injections into the brain have been shown to increase feeding and drinking behaviors; produce sleep, wakefulness, and arousal disturbances; produce analgesia; activate the hypothalamic-pituitary axis; elicit gastric acid secretion; and alter temperature regulating mechanisms (3,14,19,21,23,25,42,44,45,48).…”

“…Hcrt-1 injections into the brain have been shown to increase feeding and drinking behaviors; produce sleep, wakefulness, and arousal disturbances; produce analgesia; activate the hypothalamic-pituitary axis; elicit gastric acid secretion; and alter temperature regulating mechanisms (3,14,19,21,23,25,42,44,45,48). Hcrt-1 neurons have been shown to contribute to an extensive innervation of forebrain, brain stem, and spinal cord structures (10,33,42,46,47), and receptors to Hcrt-1 have been demonstrated throughout the neuraxis (28).…”