Elsevier

Peptides

Volume 26, Issue 10, October 2005, Pages 1952-1964
Peptides

Review
Involvement of melanocortin-4 receptor in anxiety and depression

https://doi.org/10.1016/j.peptides.2004.11.029Get rights and content

Abstract

The melanocortins, which are derived from proopiomelanocortin, have a variety of physiological functions mediated membrane surface receptors. To date, five subtypes have been cloned. With the cloning of melanocortin receptors, studies with genetic models, and development of selective compounds, the physiological roles of the five melanocortin receptors have begun to be understood. The melanocortin-4 receptor (MC4R), which is predominantly expressed in the central nervous system, has in particular become the focus of much attention in recent years because of the critical roles it plays in a wide range of functions, including feeding, sexual behavior, and stress. Recent development of selective antagonists for the MC4R has provided pharmacological evidence that blockade of MC4R could be a useful way of alleviating numerous conditions such as anxiety/depression, pain, and addiction to drugs of abuse.

Introduction

Adrenocorticotropin (ACTH) and α-, β-, and γ-melanocyte-stimulating hormones (α-, β-, and γ-MSH) are derived from proopiomelanocortin (POMC) by enzymatic processing, and are collectively called melanocortins. Melanocortins are involved in a wide range of physiological functions, including memory and/or learning [36], thermoregulation [74], analgesia [107], [108], stress responses [2], [35], [105], feeding behavior [84], inflammation [23], and pigmentation [96]. Melanocortins act via five receptor subtypes (MC1R–MC5R), all of which belong to the G-protein coupled receptor (GPCR) superfamily, and are positively coupled to adenylate cyclase [28], [29], [45], [46], [73]. Based on their distribution and the results of studies with selective agonists or antagonists for each receptor subtype, the physiological functions mediated by each receptor subtype have begun to be understood. Peripheral MC1R is thought to play roles in anti-inflammatory effect and in pigmentation, while MC2R, which is mainly expressed in adrenal cortex, mediates ACTH-induced steroidogenesis [73]. In the brain, MC3R and melanocortin-4 receptor (MC4R) are mainly expressed, with little expression of MC5R. Of these, the MC4R has become the focus of much attention in recent years because of the critical roles it plays in the central regulation of feeding behavior and energy expenditure [42], [54], [57]. In addition to feeding behavior, the MC4R has been reported to play important roles in addiction to drugs of abuse [5], [20], [53], pain processes [107], [108], and regulation of the activity of hypothalamus–pituitary–adrenal (HPA) axis [67], [105]. Moreover, the recent development of a nonpeptide, specific, and systemically active MC4R antagonist has revealed the involvement of the MC4R in emotional states such as anxiety and depression, and pharmacological roles of MC4R antagonist in rodent models of these disorders have been elucidated [24]. This article briefly reviews current knowledge of the melanocortin system and melanocortin receptors, and then focuses on the roles of MC4R in stress and stress-related disorders. In addition, the MC4R as a possible therapeutic target for the treatment of stress-related disorders such as anxiety and depression is discussed.

Section snippets

Melanocortin peptides

The melanocortins are posttranslational products of the POMC prohormone, whose cDNA sequence was first reported in 1979 [75]. The sequence of POMC was subsequently determined in several species shortly thereafter, including human [27] and rat [39]. Posttranslational processing of the POMC prohormone is performed at dibasic cleavage sites by the prohormone convertases PC1 and PC2 in a tissue-specific manner, which could be explained by the relative expression of these convertases [11], [85]. The

Feeding and energy homeostasis

There are several lines of evidence that the melanocortinergic system is involved in feeding behavior and energy expenditure, and that the MC4R is responsible for these. Although many studies have suggested a role for melanocortins in the inhibition of food intake, on the basis of the observation that injection of ACTH inhibited food intake and POMC mRNA level was regulated by metabolic state [84], [98], it was not until 1997 that researchers took greater notice of the brain melanocortin system

Stress-related behaviors and regulation of the HPA axis

Of melanocortins, it has been reported that α-MSH and ACTH act as neurotramsmitters or neuromodulators in the brain [14], and the relationship between α-MSH and ACTH, and stress has been documented. α-MSH and ACTH induce excessive grooming behavior in rats, a rodent behavioral response to stressful situations [2], [35], and antiserum to ACTH reduces novelty-induced grooming [41]. Thus, grooming behavior may be indicative of activation of the central melanocortin system during conditions of mild

Conclusion

Over the last decade, cloning of melanocortin receptor subtypes, studies with genetic models, and development of melanocortin receptor subtype selective compounds have opened new avenues in study of the physiological roles of each melanocortin receptor subtype. Researchers have paid much attention to the brain MC4R, in particular, since the finding of involvement of the MC4R in feeding and energy homeostasis in 1997, and this finding has prompted pharmaceutical industry to develop selective

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      In total, 142 articles were selected as references. The MC4R has been recognized as the main mediator of the melanocortin system influence on the stress response and negative emotional states, including anxiety and depression [8,9], identifying the MC4R as a potential target for the treatment of these psychiatric conditions. The MC4Rs are expressed in the limbic system and, particularly, in several nuclei of the amygdala, such as central and basolateral nuclei, lateral septal nucleus, hippocampus and entorhinal cortex [26].

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