Differential influence of a selective melanocortin MC4 receptor antagonist (HS014) on melanocortin-induced behavioral effects in rats

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Abstract

We injected i.c.v. the natural agonist α-MSH (melanocyte-stimulating hormone) and the first selective melanocortin MC4 receptor antagonist HS014 (cyclic [AcCys11, d-Nal14, Cys18, Asp-NH222]-β-MSH(11–22) in rats and scored a number of behavioral effects which have been related to the melanocortic peptides. The results showed that HS014 (5 μg/rat) completely blocked α-MSH (3 and 5 μg/rat)-induced grooming, yawning and stretching. Penile erections induced by α-MSH were, however, only partially blocked by HS014. Injections of α-MSH decreased food intake in food-deprived rats, whereas HS014 increased food intake. When the peptides were given together, the food intake was similar to that of saline treated controls. Locomotion/exploration and resting were not influenced by either peptide. Our data show that exogenous α-MSH decreases food intake, and that an endogenous central melanocortinergic inhibitory tone on feeding prevails which can be blocked with HS014, leading to an increase in food intake. Our data also provide evidence that grooming, stretching and yawning in rats may be mediated by the melanocortin MC4 receptor, whereas penile erections might perhaps be mediated by some other melanocortin receptor.

Introduction

The natural melanocortin peptides [MSH (melanocyte-stimulating hormone)/ACTH (adrenocorticotrophic hormone)] are known to exert a variety of physiological effects of both peripheral and, perhaps more importantly, central origin. The effects of MSH/ACTH peptides on pigmentation and steroidoneogenesis are fairly well characterized, whereas the mechanisms behind the central MSH/ACTH syndrome (Bertolini et al., 1988), including effects on grooming, stretching, yawning, pyretic control, pain perception, attention, learning and memory, ingestive, sexual and social behaviors, are less well understood (Eberle, 1988; O'Donohue and Dorsa, 1982).

Five melanocortin receptor subtypes have been cloned (Chhajlani et al., 1993; Chhajlani and Wikberg, 1992; Gantz et al., 1993a, Gantz et al., 1993b; Mountjoy et al., 1992). The melanocortin MC1 receptor is found in melanoma cells, where it has a role in mediating pigmentation. The melanocortin MC2 receptor (or ACTH) receptor is found in the adrenal glands where it mediates the effects of ACTH. The melanocortin MC3 receptor is primarily found in the CNS (central nervous system) (Gantz et al., 1993a) but its physiological function is still more or less unknown. The melanocortin MC4 receptor has only been found in the brain, where it is widely distributed in several areas, including the cortex, thalamus, hypothalamus, brain stem and spinal cord (Gantz et al., 1993b; Mountjoy et al., 1994). The melanocortin MC4 receptor has recently been related to weight homeostasis:-melanocortin MC4 receptor `knock-out' mice develop obesity (Huszar et al., 1997) and injection of MSH peptides inhibits feeding behavior (Vergoni et al., 1986, Vergoni et al., 1990; Fan et al., 1997). The melanocortin MC5 receptor has a wide peripheral distribution and is believed to participate in the regulation of exocrine gland function (Chen et al., 1997).

The natural melanocortin peptides are not selective for any of the melanocortin receptor subtypes, with the exception that α-MSH is somewhat selective for the melanocortin MC1 receptor and ACTH is selective for the melanocortin MC2 receptor. The lack of subtype-selective antagonists for the melanocortin receptors has hampered the clarification of the physiological mechanisms behind the various effects of the melanocortin peptides. The development of melanocortin MC3 and MC4 receptor antagonists like SHU9119 (cyclic [Nle4, Asp5, d-Nal7, Lys10]α-MSH-(4–10)) (Hruby et al., 1995) and some ACTH-(4–10) analogues (Adan et al., 1994b) has opened new possibilities to clarify the mechanism of action of the melanocortins. However, these substances are not selective for any of the melanocortin receptor subtypes (Hruby et al., 1995; Schiöth et al., 1997b, Schiöth et al., 1997c). HS014 (cyclic [AcCys11, d-Nal14, Cys18, Asp-NH222]-β-MSH(11–22) (Schiöth et al., 1998), the first melanocortin MC4 receptor-selective antagonist, is an additional tool to elucidate the subtype-specific actions of the melanocortin receptors. HS014 is an antagonist of the melanocortin MC3 and MC4 receptors, with about 20-fold selectivity for the melanocortin MC4 receptor above the melanocortin MC3 receptor, and is a low-affinity partial agonist of the melanocortin MC1 receptor and the melanocortin MC5 receptor. HS014 is highly potent in increasing food intake in free-feeding rats (Kask et al., 1998).

In this study, we used the natural agonist α-MSH and HS014 to investigate a number of behavioral effects which have been related to the melanocortin peptides.

Section snippets

Animals and surgery

Adult male rats of a Wistar strain (Harlan Nossan, Correzzana, MI, Italy), weighing 200–220 g, were housed 4–5 per cage (25×40×15 cm Makrolon cages) in climatized colony rooms (21±1°C; 60% humidity) with food and water continuously available. Stainless-steel guide cannulae (23 gauge) (Plastic Products, Roanoke, VA, USA) were stereotaxically implanted into both lateral ventricles, to a depth of 0.5 mm above the ventricles (measured in millimeters from the bregma: AP=−0.8; L=1.4; V=3.25) (Paxinos

Influence of HS014 on α-MSH-induced behavioral syndrome

We injected α-MSH and HS014 i.c.v. in fed ad libitum rats, and scored grooming, penile erections, yawning and stretching. Data are shown in Fig. 1. As expected, α-MSH significantly increased the number of yawning [F(5,42)=21.6; P<0.001] and stretching episodes [F(5,42)=461.85; P<0.001] and the grooming score [F(5,42)=60.75; P<0.001] at both the doses tested (3 and 5 μg/rat) while the number of penile erections was increased [F(5,42)=13.02; P<0.001] only at the highest dose. HS014 (5 μg/rat) did

Discussion

The melanocortin peptides exert as do many other neuropeptides, a broad array of effects whose underlying mechanisms are not fully understood. It has been known for a long time that multiple melanocortin receptors may be involved in mediating the various central effects of melanocortins. However, the cloning and localization of distinct melanocortin receptor subtypes in the CNS (the melanocortin MC3 and MC4 receptors are the melanocortin receptors which are most abundantly expressed in the

Acknowledgements

This study was supported by grants from the Swedish MRC (04X-05957) and the Swedish Society for Medical Research, and from Ministero dell'Università e della Ricerca Scientifica e Tecnologica, Roma, Italy.

References (32)

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Also corresponding author. E-mail: [email protected].

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