Histaminergic neurons are involved in the orexigenic effect of orexin-A.
Orexin-A is an orexigenic peptide expressed mainly in the hypothalamus. Orexin-A increases and anti-orexin-A antibodies decrease food intake. However, the exact mechanism by which orexin-A exerts its orexigenic action is not fully elucidated. The histaminergic system is known to play a role in feeding behavior and we hypothesized that it could be involved in the orexigenic effect of orexin-A. To study this, we used histamine knockout animals and pharmacological blockade of the histaminergic system and studied the effect of orexin-A on feeding behavior and gene expression of neuropeptide Y (NPY). Orexin-A was administered intracerebroventricularly and food intake measured in wild-type, histamine H(1)-receptor knockout or histidine decarboxylase knockout mice. Additionally, we administered orexin-A to wild-type mice with pharmacologically blocked H(1)-receptors or pharmacologically stimulated autoinhibitory H(3)-receptors. By quantitative real-time PCR we measured the effect of orexin-A on NPY mRNA expression in wild-type and knockout mice. Orexin-A dose-dependently stimulated food intake when administered to wild-type mice in doses up to 0.03 microg. Orexin-A in a dose of 0.01 microg increased food intake 10-fold in wild-type mice, whereas no increase in food intake was seen in either knockout mice or pharmacologically manipulated mice. Orexin-A increased NPY mRNA 4-fold in wild-type mice, whereas no change was observed in knockout mice. We conclude that the orexigenic effect of orexin-A is dependent on an intact histaminergic neuronal system and seems to involve an H(1)-receptor mechanism.
Jørgensen
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EA
Department of Medical Physiology, Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
Knigge
U
U
Watanabe
T
T
Warberg
J
J
Kjaer
A
A
D000818:Animals; D001345:Autoradiography; D004435:Eating / Q000187:drug effects* / Q000502:physiology*; D006632:Histamine / Q000502:physiology*; D006633:Histamine Antagonists / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology*; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D011969:Receptors, Histamine H1 / Q000187:drug effects; D018100:Receptors, Histamine H3 / Q000187:drug effects; D018013:Receptors, Neuropeptide / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D011969:Receptors, Histamine H1; D018100:Receptors, Histamine H3; D018013:Receptors, Neuropeptide; D006632:Histamine