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The Journal of Neuroscience, November 12, 2003, 23(32):10351-10358
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Behavioral/Systems/Cognitive
 -Melanocyte-Stimulating Hormone Stimulates Oxytocin Release from the Dendrites of Hypothalamic Neurons While Inhibiting Oxytocin Release from Their Terminals in the Neurohypophysis
Nancy Sabatier,1
Céline Caquineau,1
Govindan Dayanithi,2
Philip Bull,1
Alison J. Douglas,1
Xiao Ming M. Guan,3
Michael Jiang,3
Lex Van der Ploeg,3 and
Gareth Leng1
1Department of Biomedical Sciences, University of Edinburgh Medical School, Edinburgh EH8 9XD, United Kingdom, 2 Institut National de la Santéet de la Recherche Médicale 583, University of Montpellier II, Montpellier, Cedex 5, France, and 3Departments of Medicinal Chemistry and Obesity Research, Merck Research Laboratories, Rahway, New Jersey 07065
The peptides  -melanocyte stimulating hormone (-MSH) and oxytocin, when administered centrally, produce similar behavioral effects. -MSH induces Fos expression in supraoptic oxytocin neurons, and -MSH melanocortin-4 receptors (MC4Rs) are highly expressed in the supraoptic nucleus, suggesting that -MSH and oxytocin actions are not independent. Here we investigated the effects of -MSH on the activity of supraoptic neurons. We confirmed that -MSH induces Fos expression in the supraoptic nucleus when injected centrally and demonstrated that -MSH also stimulates Fos expression in the nucleus when applied locally by retrodialysis. Thus -MSH-induced Fos expression is not associated with electrophysiological excitation of supraoptic neurons because central injection of -MSH or selective MC4 receptor agonists inhibited the electrical activity of oxytocin neurons in the supraoptic nucleus recorded in vivo. Consistent with these observations, oxytocin secretion into the bloodstream decreased after central injection of -MSH. However, MC4R ligands induced substantial release of oxytocin from dendrites in isolated supraoptic nuclei. Because dendritic oxytocin release can be triggered by changes in [Ca2+]i, we measured [Ca2+]i responses in isolated supraoptic neurons and found that MC4R ligands induce a transient [Ca2+]i increase in oxytocin neurons. This response was still observed in low extracellular Ca2+ concentration and probably reflects mobilization of [Ca2+]i from intracellular stores rather than entry via voltage-gated channels. Taken together, these results show for the first time that a peptide, here -MSH, can induce differential regulation of dendritic release and systemic secretion of oxytocin, accompanied by dissociation of Fos expression and electrical activity.
Key words: -melanocyte-stimulating hormone; supraoptic nucleus; oxytocin; dendritic release; electrical activity; Fos expression; [Ca2+]i
Received June 19, 2003;
revised September 23, 2003;
accepted September 24, 2003.
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