γ1-MSH

Opposite effects of gamma(1)- and gamma(2)-melanocyte stimulating hormone on regulation of the dopaminergic mesolimbic system in rats.[Pubmed:15135895]

Neurosci Lett. 2004 May 6;361(1-3):68-71.

By use of the brain microdialysis technique we show that administration of gamma(1)-melanocyte stimulating hormone (gamma(1)-MSH) into the ventral tegmental area of anaesthetized rats causes an increase in the release of extracellular dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the nucleus accumbens, while gamma(2)-MSH causes the opposite effect. Moreover, gamma(2)-MSH pre-treatment considerably reduced the gamma(1)-MSH-induced effects. Our findings suggest an opposing action of two gamma-MSH-activated pathways on the mesolimbic dopaminergic system, which could be important in the maintenance of a balanced psychoactivation state.

Autoradiographic discrimination of melanocortin receptors indicates that the MC3 subtype dominates in the medial rat brain.[Pubmed:9813305]

Brain Res. 1998 Nov 9;810(1-2):161-71.

In the present study, we developed an autoradiographic method to visualize the distribution of melanocortin (MC) receptors 3 and 4 in sagittal sections of the rat brain. The method takes advantage of the MC3 and MC4 receptor selective compounds, gamma1-MSH and HS014. First, we characterized the binding of gamma1-MSH, HS014 and the radioligand [125I]NDP-MSH to the rat MC3 and MC4 receptors expressed in COS cells. [125I]NDP-MSH was found to be non-selective, whereas gamma1-MSH showed a 40-fold preference for the rat MC3 receptor, and HS014 an over 300-fold preference to the rat MC4 receptor. Second, to discriminate between the MC3 and MC4 receptors in rat brain sections, the sections were incubated with [125I]NDP-MSH in the presence of graded concentrations of the MC3 selective ligand, gamma1-MSH, or the MC4 selective ligand, HS014. From the autoradiograms thus made, competition curves of gamma1-MSH and HS014 could be constructed for different regions of the rat brain. Our results indicate that in the nucleus accumbens shell, the medial preoptic area, and the ventromedial nucleus of the hypothalamus, there is a clear dominance of the MC3 receptor, whereas in the lateral septum and the olfactory tubercle, there seem to be present both MC3 and MC4 receptors, although the MC3 receptor may still be the dominating subtype. In the optic layer of the superior colliculus, our data indicate a more abundant expression of the MC4 receptor. In the ventral tegmental area, there might be an additional MSH-peptide binding site of unknown origin.

Melanocortins and cardiovascular regulation.[Pubmed:9845266]

Eur J Pharmacol. 1998 Oct 30;360(1):1-14.

The melanocortins form a family of pro-opiomelanocortin-derived peptides that have the melanocyte-stimulating hormone (MSH) core sequence, His-Phe-Arg-Trp, in common. Melanocortins have been described as having a variety of cardiovascular effects. We review here what is known about the sites and mechanisms of action of the melanocortins with respect to their effects on cardiovascular function, with special attention to the effects of the gamma-melanocyte-stimulating hormones (gamma-MSHs). This is done in the context of present knowledge about agonist selectivity and localisation of the five melanocortin receptor subtypes cloned so far. gamma2-MSH, its des-Gly12 analog (= gamma1-MSH) and Lys-gamma2-MSH are 5-10 times more potent than adrenocorticotropic hormone-(4-10)(ACTH-(4-10)) to induce a pressor and tachycardiac effect following intravenous administration. The Arg-Phe sequence near the C-terminal seems to be important for full in vivo intrinsic activity. Related peptides with a C-terminal extension with (gamma3-MSH) or without the Arg-Phe sequence (alpha-MSH, as well as the potent alpha-MSH analog, [Nle4,D-Phe7]alpha-MSH), are, however, devoid of these effects. In contrast, ACTH-(1-24) has a depressor effect combined with a tachycardiac effect, effects which are not dependent on the presence of the adrenals. Although the melanocortin MC3 receptor is the only melanocortin receptor subtype for which gamma2-MSH is selective, in vivo and in vitro structure-activity data indicate that it is not via this receptor that this peptide and related peptides exert either their pressor and tachycardiac effects or their extra- and intracranial blood flow increasing effect. We review evidence that the pressor and tachycardiac effects of the gamma-MSHs are due to an increase of sympathetic outflow to the vasculature and the heart, secondary to activation of centrally located receptors. These receptors are most likely localised in the anteroventral third ventricle (AV3V) region, a brain region situated outside the blood-brain barrier, and to which circulating peptides have access. These receptors might be melanocortin receptors of a subtype yet to be identified. Alternatively, they might be related to other receptors for which peptides with a C-terminal Arg-Phe sequence have affinity, such as the neuropeptide FF receptor and the recently discovered FMRFamide receptor. Melanocortin MC4 receptors and still unidentified receptors are part of the circuitry in the medulla oblongata which is involved in the depressor and bradycardiac effect of the melanocortins, probably via interference with autonomic outflow. Regarding the effects of the gamma-MSHs on cortical cerebral blood flow, it is not yet clear whether they involve activation of the sympathetic nervous system or activation of melanocortin receptors located on the cerebral vasculature. The depressor effect observed following intravenous administration of ACTH-(1-24) is thought to be due to activation of melanocortin MC2 receptors whose location may be within the peripheral vasculature. Melanocortins have been observed to improve cardiovascular function and survival time in experimental hemorrhagic shock in various species. Though ACTH-(1-24) is the most potent melanocortin in this model, alpha-MSH and [Nle4,D-Phe7]alpha-MSH and ACTH-(4-10) are quite effective as well. As ACTH-(4-10) is a rather weak agonist of all melanocortin receptors, it is difficult to determine via which of the melanocortin receptors the melanocortins bring about this effect. Research into the nature of the receptors involved in the various cardiovascular effects of the melanocortins would greatly benefit from the availability of selective melanocortin receptor antagonists.