Melanocyte-Stimulating Hormone Stimulates Oxytocin Release from the Dendrites of Hypothalamic Neurons While Inhibiting Oxytocin Release from Their Terminals in the Neurohypophysis (original) (raw)
The Journal of Neuroscience
Both central ␣-melanocyte-stimulating hormone and corticotropin-releasing hormone (CRH) have been implicated in feeding and neuroendocrine mechanisms. The anatomical overlap and functional similarities between these two neurotransmitter systems led to the hypothesis that CRH might act as one of the mediators of the central actions of the melanocortin system. By double-labeling in situ hybridization, a subpopulation of CRH neurons in the paraventricular nucleus of the hypothalamus (PVN) were shown to contain the melanocortin-4 receptor (MC4R), concentrated in the ventromedial part of the parvicellular PVN (up to 33%). Intracerebroventricular injection of melanocortin agonist MTII to conscious and freely moving rats induced a rapid induction of CRH gene transcription in the PVN. This effect was accompanied by a rise in plasma corticosterone levels in a dose-and time-dependent manner, with the maximum response observed 30 min after MTII injection. MTII (0.5 nmol)-induced increase in plasma corticosterone was attenuated by the selective MC4R antagonist HS014 (0.25-1.0 nmol) and nonselective CRH receptor antagonist ␣-helical-CRH 9-41 (0.125-0.5 nmol) in a dose-dependent manner. Moreover, the anorectic effect of MTII was evaluated at 1, 2, and 24 hr after intracerebroventricular injection. Approximately half of the inhibitory effect of MTII (0.5 nmol) on food intake was reversed by pretreatment with ␣-helical-CRH 9-41 at 0.25 and 0.5 nmol doses. Collectively, these results provide evidence that CRH acts as a downstream mediator of melanocortin signaling and contributes to the mechanisms by which the central melanocortin system controls feeding and neuroendocrine responses.
α-Melanocyte-stimulating hormone (α-MSH) release from perifused rat hypothalamic slices
Brain Research, 1987
A perifusion system was developed to investigate the control of a-melanocyte-stimulating hormone (a-MSH) release from rat brain. Hypothalamic slices were perifused with Krebs-Ringer bicarbonate (KRB) medium supplemented with glucose, bacitracin and bovine serum albumine. Fractions were set apart every 3 min and a-MSH levels were measured by means of a specific and sensitive radioimmunoassay method. Hypothalamic tissue in normal KRB medium released a-MSH at a constant rate corresponding to 0.1% of the total hypothalamic content per 3 min. The basal release was not altered by Ca 2+ omission in the medium or addition of the sodium channel blocker tetrodotoxine (TTX). Depolarizing agents such as potassium (50 mM) and veratridine (50/~M), which is known to increase Na + conductance, significantly stimulated a-MSH release in a Ca2+-dependent manner. When Na+-channels were blocked by TTX (0.5/~M) the stimulatory effect of veratridine was completely abolished whereas the K+-evoked release was unaffected. These findings suggest that: (1) voltage-dependent sodium channels are present on a-MSH hypothalamic neurons; (2) depolarization by K + induces a marked stimulation of a-MSH release; (3) K +-and veratridine-evoked releases are calcium-dependent. Altogether, these data provide evidence for a neurotransmitter or neuromodulator role for a-MSH in rat hypothalamus.
Neuroendocrinology, 2004
There is evidence that ·-melanocyte-stimulating hormone (·-MSH) has immunomodulatory and anti-inflammatory actions within the brain. In this study, we tested whether these actions are due to inhibition of the synthesis of nitric oxide (NO) and prostaglandins induced by lipopolysaccharide (LPS). Since melanocortin subtype MC4 receptor has been detected in the hypothalamus, we investigated the effect of central administration of ·-MSH and HS024 (a selective MC4 receptor antagonist) on the gene expression of inducible, neuronal and endothelial NO synthase (iNOS, nNOS and eNOS) and on cyclooxygenase (COX-1 and COX-2) expression in the mediobasal hypothalamus (MBH) of LPS-treated male Wistar rats. Peripheral administration of LPS (250 Ìg/rat, Hypothalamic Anti-Inflammatory Effects of ·-MSH Neuroendocrinology 2004;79:278-286 279
Journal of Neuroendocrinology, 2006
The present series of studies aimed to further our understanding of the role of melanin-concentrating hormone (MCH) neurones in the central regulation of luteinising hormone (LH) release in the female rat. LH release was stimulated when MCH was injected bilaterally into the rostral preoptic area (rPOA) or medial preoptic area (mPOA), but not when injected into the zona incerta (ZI), of oestrogen-primed ovariectomised rats. In rats that were steroid-primed to generate a surge-like release of LH, MCH administration into the ZI blocked this rise in LH release: no such effect occurred when MCH was injected into the rPOA or mPOA. In vitro, MCH stimulated gonadotrophin-releasing hormone (GnRH) release from hypothalamic explants. Double-label immunohistochemistry showed GnRH-immunoreactive neurones in the vicinity of and intermingled with immunoreactive MCH processes. MCH is the endogenous ligand of the MCH type 1 receptor (MCH1-R). Previously, we have shown a role for melanocortin-5 receptors (MC5-R) in the stimulatory action of MCH, so we next investigated the involvement of both MCH1-R and/or MC5-R in mediating the actions of MCH on GnRH and hence LH release. The stimulatory action of MCH in the rPOA was inhibited by administration of antagonists for either MCH1-R or MC5-R. However, in the mPOA, the action of MCH was blocked only by the MC5-R antagonist. LH release was stimulated by an agonist for MC5-R injected into the rPOA or mPOA; this was blocked by the MC5-R antagonist but not the MCH1-R antagonist. These results indicate that both MCH1-R and MC5-R are involved in the central control of LH release by MCH.
Brain Research, 1987
Melanin-concentrating hormone (MCH)-containing neurons have recently been localized in the dorsolateral region of the rat hypothalamus, an area where the second a-MSH system is found which contains only a-MSH and none of the pro-opiomelanocortin (POMC)-related peptides. In order to study the morphological relationships between the MCH and a-MSH neuronal systems, we have studied the immunocytochemical localization of both MCH and a-MSH in the rat hypothalamus. The same study was also performed in the human hypothalamus where there is only one a-MSH system which contains a-MSH as well as the other POMC-related peptides (first a-MSH system), In the rat dorsolateral hypothalamus, we could demonstrate that most neuronal cell bodies stained for MCH also contained immunoreactive a-MSH. In the human hypothalamus, neuronal cell bodies stained for MCH were observed only in the periventricular area whereas cell bodies containing a-MSH were exclusively located in the infundibular (arcuate) nucleus. In the rat, immunoelectron microscopy showed labelling for MCH in the dense core vesicles of positive neurons and double-staining techniques clearly demonstrated that both immunoreactive MCH and a-MSH could be consistently detected in the same dense core vesicles. These ultrastructurai studies then suggest that these two peptides should be released simultaneously from neurons located in the rat dorsolateral hypothalamus.
Melanin-concentrating hormone: unique peptide neuronal system in the rat brain and pituitary gland
Proceedings of the National Academy of Sciences, 1986
A unique neuronal system was detected in the rat central nervous system by immunohistochemistry and radioimmunoassay with antibodies to salmon melanin-concentrating hormone (MCH). MCH-like immunoreactive (MCH-LI) cell bodies were confined to the hypothalamus. MCH-LI fibers were found throughout the brain but were most prevalent in hypothalamus, mesencephalon, and pons-medulla regions. High concentrations of MCH-LI were measured in the hypothalamic medial forebrain bundle (MFB), posterior hypothalamic nucleus, and nucleus of the diagonal band. Reversed-phase high-performance liquid chromatography of MFB extracts from rat brain indicate that MCH-like peptide from the rat has a different retention time than that of the salmon MCH. An osmotic stimulus (2% NaCI as drinking water for 120 hr) caused a marked increase in MCH-LI concentrations in the lateral hypothalamus and neurointermediate lobe. The present studies establish the presence of MCH-like peptide in the rat brain. The MCH-LI neuronal system is well situated to coordinate complex functions such as regulation of water intake.
Melanin-concentrating hormone: unique peptide neuronal systems in the rat brain and pituitary gland
1986
A unique neuronal system was detected in the rat central nervous system by immunohistochemistry and radioimmunoassay with antibodies to salmon melanin-concentrating hormone (MCH). MCH-like immunoreactive (MCH-LI) cell bodies were confined to the hypothalamus. MCH-LI fibers were found throughout the brain but were most prevalent in hypothalamus, mesencephalon, and pons-medulla regions. High concentrations of MCH-LI were measured in the hypothalamic medial forebrain bundle (MFB), posterior hypothalamic nucleus, and nucleus of the diagonal band. Reversed-phase high-performance liquid chromatography of MFB extracts from rat brain indicate that MCH-like peptide from the rat has a different retention time than that of the salmon MCH. An osmotic stimulus (2% NaCI as drinking water for 120 hr) caused a marked increase in MCH-LI concentrations in the lateral hypothalamus and neurointermediate lobe. The present studies establish the presence of MCH-like peptide in the rat brain. The MCH-LI neuronal system is well situated to coordinate complex functions such as regulation of water intake.
A melanocortin agonist reduces neuronal firing rate in rat hypothalamic slices
Neuroscience Letters, 2000
Bath application of a-melanocyte stimulating hormone (a -MSH) to rat hypothalamic slices inhibited the spontaneous ®ring rate of continuously ®ring neurons in the ventromedial hypothalamic nucleus or paraventricular nucleus. This inhibitory effect is most likely direct and independent of synaptic transmission. The a-MSH-responsive neurons tested did not respond to neuropeptide Y (NPY) application. On the other hand, a-MSH did not inhibit the intraburst ®ring rate of phasic bursting neurons, although these bursting neurons were highly responsive to a serotonin 5HT2a/2b/2c agonist with a change of ®ring pattern to continuous ®ring and an increase in ®ring rate which was reversed by NPY. These results suggest that a change of neuronal ®ring rate may represent a neural correlate of satiety induced by anorexic agents.
Neuroscience, 2001
AbstractöHypothalamic pro-opiomelanocortin neurones have an established role in the control of feeding. While proopiomelanocortin is the precursor for at least three melanocortin peptides, K-, L-and Q-melanocyte-stimulating hormone (MSH), it has been widely assumed that K-MSH is the predominant ligand involved. We compared the e¡ects of centrally administered K-, L-and Q 2 -MSH on hypothalamic neuronal activation and on food intake in rats fasted for 48 h. Signi¢cant reductions in food intake were seen with K-MSH (¢rst hour) and Q 2 -MSH (second hour) but not with L-MSH. The pattern of neuronal activation, assessed by the detection of early growth response factor-1 protein, showed considerable overlap; all three melanocortins activated cells in the arcuate, ventromedial, paraventricular, periventricular and supraoptic nuclei, as well as the preoptic area. K-MSH and L-MSH produced activation in the dorsomedial nuclei while Q 2 -MSH was only weakly active here. Retrograde labelling by systemic Fluorogold injection revealed that many cells activated by MSH compounds in the arcuate, paraventricular, periventricular and supraoptic nuclei (but not dorsomedial or ventromedial) project outside the blood^brain barrier and are therefore likely to include neuroendocrine cells. Desacetyl-K-MSH, which has previously been reported to lack e¡ects on feeding, produced no discernible neuronal activation in the hypothalamus. Our ¢nding that both the pattern of neuronal activation and the distribution of neuroendocrine cells activated in response to these closely related peptides show only partial overlap suggests that, in addition to common pathways, there may exist distinct hypothalamic circuits activated by di¡erent pro-opiomelanocortin products. The slower time course of Q 2 -MSH-versus K-MSH-induced suppression of feeding provides further support for the notion that the biological responses to individual melanocortin peptides may involve distinct neuronal mechanisms.
Brain Research, 1990
The neuropeptide a-melanocyte-stimulating hormone (a-MSH) is synthesized by discrete populations of hypothalamic neurons which project in different brain regions including the cerebral cortex, hippocampus and amygdala nuclei. The purpose of the present study was to identify the a-MSH-immmunoreactive species contained in these different structures and to compare the ionic mechanisms underlaying ct-MSH release at the proximal and distal levels, i.e. within the hypothalamus and amygdala nuclei, respectively. The molecular forms of a-MSH-related peptides stored in discrete areas of the brain were characterized by combining high-performance liquid chromatography (HPLC) separation and radioimmunoassay detection. In mediobasal and dorsolateral hypothalamic extracts, HPLC analysis confirmed the existence of a major immunoreactive peak which co-eluted with the synthetic des-Na-acetyl a-MSH standard. In contrast, 3 distinct forms of immunoreactive a-MSH, which exhibited the same retention times as synthetic des-, mono-and di-acetyl a-MSH, were resolved in amygdala nuclei, hippocampus, cortex and medulla oblongata extracts. The proportions of acetylated a-MSH (authentic a-MSH plus diacetyl a-MSH) contained in these extrahypothalamic structures were, respectively, 78, 80, 60 and 92% of the total a-MSH immunoreactivity. In order to compare the ionic mechanisms underlaying a-MSH release from hypothalamic and extrahypothalamic tissues, we have investigated in vitro the secretion of a-MSH by perifused slices of hypothalamus and amygdala nuclei. High potassium concentrations induced a marked increase of a-MSH release from both tissue preparations. However, a higher concentration of KC1 was required to obtain maximal stimulation of amygdala nuclei (90 mM) than hypothalamic tissue (50 mM). The effect of depolarizing concentrations of KCI was totally suppressed in the absence of Ca 2÷, indicating that high-K + induced the opening of voltage-operated Ca 2+ (VOC) channels. Veratridine (50 ~M), a depolarizing agent which activates Na ÷ conductances, caused a robust stimulation of a-MSH release from hypothalamic slices but had virtually no effect on amygdala nuclei, to-Conotoxin (1/~M), a peptide toxin which, blocks Land N-type VOC channels, caused a slight reduction of K÷-evoked a-MSH release from hypothalamic slices but induced a dramatic decrease of a-MSH release from amygdala nuclei. These data suggest that acetylation of a-MSH to generate the biologically active forms of the peptide is a slow process which occurs gradually during axonal transport. Our results also indicate that release of a-MSH at the hypothalamic level mainly results from activation of T-type VOC channels whereas, in the amygdala nuclei, Land (or) N-type VOC channels are involved in the regulation of a-MSH secretion.