α-Melanocyte-Stimulating Hormone Stimulates Oxytocin Release from the Dendrites of Hypothalamic Neurons While Inhibiting Oxytocin Release from Their Terminals in the Neurohypophysis

Abstract

The peptides α-melanocyte stimulating hormone (α-MSH) and oxytocin, when administered centrally, produce similar behavioral effects. α-MSH induces Fos expression in supraoptic oxytocin neurons, and α-MSH melanocortin-4 receptors (MC4Rs) are highly expressed in the supraoptic nucleus, suggesting that α-MSH and oxytocin actions are not independent. Here we investigated the effects of α-MSH on the activity of supraoptic neurons. We confirmed that α-MSH induces Fos expression in the supraoptic nucleus when injected centrally and demonstrated that α-MSH also stimulates Fos expression in the nucleus when applied locally by retrodialysis. Thus α-MSH-induced Fos expression is not associated with electrophysiological excitation of supraoptic neurons because central injection of α-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 α-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 [Ca 2+ ] i , we measured [Ca 2+ ] i responses in isolated supraoptic neurons and found that MC4R ligands induce a transient [Ca 2+ ] i increase in oxytocin neurons. This response was still observed in low extracellular Ca 2+ concentration and probably reflects mobilization of [Ca 2+ ] i from intracellular stores rather than entry via voltage-gated channels. Taken together, these results show for the first time that a peptide, here α-MSH, can induce differential regulation of dendritic release and systemic secretion of oxytocin, accompanied by dissociation of Fos expression and electrical activity.