Involvement of melanocortin-4 receptor in anxiety and depression

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.

[1]  T. Dinan,et al.  Vasopressin and the regulation of hypothalamic-pituitary-adrenal axis function: implications for the pathophysiology of depression. , 1998, Life sciences.

[2]  J. Wikberg,et al.  Evidence for involvement of the melanocortin MC4 receptor in the effects of leptin on food intake and body weight. , 1998, European journal of pharmacology.

[3]  L. Brady Stress, antidepressant drugs, and the locus coeruleus , 1994, Brain Research Bulletin.

[4]  T. Hökfelt,et al.  The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[5]  S. File,et al.  Intraventricular ACTH reduces social interaction in male rats , 1980, Pharmacology Biochemistry and Behavior.

[6]  JaneR . Taylor,et al.  Molecular and Behavioral Interactions Between Central Melanocortins and Cocaine , 2003, Journal of Pharmacology and Experimental Therapeutics.

[7]  H. Vaudry,et al.  Central-type benzodiazepines inhibit release of α-melanocyte-stimulating hormone from the rat hypothalamus , 1991, Neuroscience.

[8]  G. Barsh,et al.  Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. , 1997, Science.

[9]  F. Bloom,et al.  Corticotropin releasing factor (CRF): immunoreactive neurones and fibers in rat hypothalamus , 1982, Regulatory Peptides.

[10]  A. G. Roseberry,et al.  Transgenic Mice Expressing Green Fluorescent Protein under the Control of the Melanocortin-4 Receptor Promoter , 2003, The Journal of Neuroscience.

[11]  N. Seidah,et al.  PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[12]  G. Aguilera,et al.  Vasopressinergic regulation of the hypothalamic–pituitary–adrenal axis: implications for stress adaptation , 2000, Regulatory Peptides.

[13]  G. Debilly,et al.  Effects of an acute immobilization stress upon proopiomelanocortin (POMC) mRNA levels in the mediobasal hypothalamus: a quantitative in situ hybridization study. , 1994, Brain research. Molecular brain research.

[14]  A. Thody,et al.  α‐MSH and the Regulation of Melanocyte Function , 1999 .

[15]  G. Pelletier,et al.  Opioid regulation of proopiomelanocortin (POMC) gene expression in the rat brain as studied by in situ hybridization , 1993, Neuropeptides.

[16]  C. Saper,et al.  Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat , 2003, The Journal of comparative neurology.

[17]  J. Wikberg,et al.  Selective melanocortin MC4 receptor blockage reduces immobilization stress-induced anorexia in rats. , 1999, European journal of pharmacology.

[18]  R. Cone,et al.  Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis , 2004, Brain Research.

[19]  R. Bertorelli,et al.  Gene expression profiling of melanocortin system in neuropathic rats supports a role in nociception. , 2003, Brain research. Molecular brain research.

[20]  B. Jacobs,et al.  Single-unit response of noradrenergic neurons in the locus coeruleus of freely moving cats. I. Acutely presented stressful and nonstressful stimuli , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  M. Nishiyama,et al.  Decreased Type 2 Corticotropin-Releasing Hormone Receptor mRNA Expression in the Ventromedial Hypothalamus during Repeated Immobilization Stress , 1999, Neuroendocrinology.

[22]  M. Palkovits,et al.  Analysis of the ACTH/β-End/α-MSH-Immunoreactive afferent input to the hypothalamic paraventricular nucleus of rat , 1984, Brain Research.

[23]  S. Chaki,et al.  Receptor binding, behavioral, and electrophysiological profiles of nonpeptide corticotropin-releasing factor subtype 1 receptor antagonists CRA1000 and CRA1001. , 1999, The Journal of pharmacology and experimental therapeutics.

[24]  Victor J. Hruby,et al.  Role of melanocortinergic neurons in feeding and the agouti obesity syndrome , 1997, Nature.

[25]  S. File,et al.  Social and exploratory behaviour in the rat after septal administration of ORG 2766 and ACTH4–10 , 1983, Psychoneuroendocrinology.

[26]  S. Burchill,et al.  Effect of alpha-melanocyte-stimulating hormone on tyrosinase activity in hair follicular and epidermal melanocytes of the mouse. , 1988, The Journal of endocrinology.

[27]  C. Sandman,et al.  Intraventricular administration of MSH induces hyperalgesia in rats , 1981, Peptides.

[28]  H. Steinbusch,et al.  Down-regulation of ACTH and glucocorticoid receptor immunoreactivity in hypothalamic arcuate neurons after adrenalectomy in the rat. , 1999, Neuroreport.

[29]  Shigeru Okuyama,et al.  Anxiolytic-Like and Antidepressant-Like Activities of MCL0129 (1-[(S)-2-(4-Fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a Novel and Potent Nonpeptide Antagonist of the Melanocortin-4 Receptor , 2003, Journal of Pharmacology and Experimental Therapeutics.

[30]  J. Wikberg,et al.  Discovery of a novel superpotent and selective melanocortin-4 receptor antagonist (HS024): evaluation in vitro and in vivo. , 1998, Endocrinology.

[31]  M. Seligman,et al.  Learned helplessness: Theory and evidence. , 1976 .

[32]  Craig W. Berridge,et al.  Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? , 1990, Brain Research Reviews.

[33]  A. Argiolas,et al.  ACTH- and α-MSH-induced grooming, stretching, yawning and penile erection in male rats: Site of action in the brain and role of melanocortin receptors , 2000, Brain Research Bulletin.

[34]  M. Parmentier,et al.  Adenosine A2A Receptor Gene Disruption Provokes Marked Changes in Melanocortin Content and Pro‐Opiomelanocortin Gene Expression , 2003, Journal of neuroendocrinology.

[35]  G. Telegdy,et al.  Involvement of Endogenous Corticotropin-Releasing Factor in Mediation of Neuroendocrine and Behavioral Effects to Alpha-Melanocyte-Stimulating Hormone , 2000, Endocrine research.

[36]  Stanley J. Watson,et al.  Identification of proopiomelanocortin neurones in rat hypothalamus by in situ cDNA-mRNA hybridization , 1983, Nature.

[37]  S. Watson,et al.  Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. , 1993, The Journal of biological chemistry.

[38]  G. Koob,et al.  Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[39]  J. Panksepp,et al.  Effects of ACTH(1–24) and ACTH/MSH(4–10) on isolation-induced distress vocalization in domestic chicks , 1990, Peptides.

[40]  J. M. Lipton,et al.  Antipyretic potency of centrally administered alpha-melanocyte stimulating hormone. , 1983, Science.

[41]  M. Jouvet,et al.  Distribution of the pro-opiomelanocortin-immunoreactive axons in relation to the serotoninergic neurons in the dorsal raphe nucleus of the rat , 1991, Neuroscience Letters.

[42]  W. Gispen,et al.  Chronic Blockade of Melanocortin Receptors Alleviates Allodynia in Rats with Neuropathic Pain , 2001, Anesthesia and analgesia.

[43]  H. Akil,et al.  Immunocytochemical localization of pro-opiomelanocortin-derived peptides in the adult rat spinal cord , 1986, Brain Research.

[44]  J. Jolles,et al.  Neuropeptides derived from pro-opiocortin: behavioral, physiological, and neurochemical effects. , 1982, Physiological reviews.

[45]  S. Chaki,et al.  Electrophysiological effects of melanocortin receptor ligands on neuronal activities of monoaminergic neurons in rats , 2003, Neuroscience Letters.

[46]  A. van Daal,et al.  Agouti: from mouse to man, from skin to fat. , 2002, Pigment cell research.

[47]  M. Mortrud,et al.  The cloning of a family of genes that encode the melanocortin receptors. , 1992, Science.

[48]  H. Schiöth,et al.  Melanocortin receptor agonist transiently increases oxygen consumption in rats , 2001, Neuroreport.

[49]  J. Wikberg,et al.  Melanocortin receptors: perspectives for novel drugs. , 1999, European journal of pharmacology.

[50]  B. McEwen,et al.  Subcutaneous implantation method for chronic glucocorticoid replacement therapy , 1979, Physiology & Behavior.

[51]  C. Nemeroff,et al.  Physiology and pharmacology of corticotropin-releasing factor. , 1991, Pharmacological reviews.

[52]  S. Sarkar,et al.  GABAergic agents prevent alpha-melanocyte stimulating hormone induced anxiety and anorexia in rats , 2003, Pharmacology Biochemistry and Behavior.

[53]  S. Watson,et al.  Molecular cloning of a novel melanocortin receptor. , 1993, The Journal of biological chemistry.

[54]  Min-Seon Kim,et al.  The Hypothalamic Melanocortin System Stimulates the Hypothalamo-Pituitary-Adrenal Axis in vitro and in vivo in Male Rats , 2002, Neuroendocrinology.

[55]  F. Bortolotti,et al.  Presence of strong glucocorticoid receptor immunoreactivity within hypothalamic and hypophyseal cells containing pro-opiomelanocortic peptides , 1992, Brain Research.

[56]  G. Griebel,et al.  Characterization of (2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine carboxamide (SSR149415), a selective and orally active vasopressin V1b receptor antagonist. , 2002, The Journal of pharmacology and experimental therapeutics.

[57]  R. Cone,et al.  Agouti and Agouti-related Protein: Analogies and Contrasts* , 2000, The Journal of Biological Chemistry.

[58]  A. Vergoni,et al.  ACTH-(1–24) and α-MSH antagonize feeding behavior stimulated by kappa opiate agonists , 1986, Peptides.

[59]  P. J. Larsen,et al.  Hypothalamic cocaine-amphetamine regulated transcript (CART) is regulated by glucocorticoids , 2003, Brain Research.

[60]  S. Cabeza de Vaca,et al.  The melanocortin receptor agonist MTII augments the rewarding effect of amphetamine in ad-libitum-fed and food-restricted rats , 2002, Psychopharmacology.

[61]  D. Charney,et al.  Norepinephrine dysfunction in depression. , 2000, The Journal of clinical psychiatry.

[62]  R. Adan,et al.  The role of central melanocortin receptors in the activation of the hypothalamus‐pituitary‐adrenal‐axis and the induction of excessive grooming , 1998, British journal of pharmacology.

[63]  Athina Markou,et al.  Assessing antidepressant activity in rodents: recent developments and future needs. , 2002, Trends in pharmacological sciences.

[64]  B. Hwang,et al.  Downregulation of Corticotropin-Releasing Factor mRNA, But Not Vasopressin mRNA, in the Paraventricular Hypothalamic Nucleus of Rats Following Nutritional Stress , 1997, Brain Research Bulletin.

[65]  L. D. van de Kar,et al.  Endocrine and receptor pharmacology of serotonergic anxiolytics, antipsychotics and antidepressants. , 1992, Life sciences.

[66]  J. Burbach,et al.  Expression of melanocortin receptors and pro-opiomelanocortin in the rat spinal cord in relation to neurotrophic effects of melanocortins. , 1999, Brain research. Molecular brain research.

[67]  A. Turnbull,et al.  Pro-opiomelanocortin processing in the hypothalamus: impact on melanocortin signalling and obesity. , 2002, The Journal of endocrinology.

[68]  H. Akil,et al.  Effects of morphine treatment on pro-opiomelanocortin systems in rat brain , 1990, Brain Research.

[69]  J. Wikberg,et al.  Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA , 1992, FEBS letters.

[70]  A. C. Chang,et al.  Structural organization of human genomic DNA encoding the pro-opiomelanocortin peptide. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[71]  Christopher P Austin,et al.  A role for the melanocortin 4 receptor in sexual function , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[72]  P. J. Larsen,et al.  Effect of acute stress on the expression of hypothalamic messenger ribonucleic acids encoding the endogenous opioid precursors preproenkephalin A and proopiomelanocortin , 1994, Peptides.

[73]  Repeated treatment with imipramine, fluvoxamine and tranylcypromine decreases the number of escape failures by activating dopaminergic systems in a rat learned helplessness test. , 2001, Life sciences.

[74]  M. Mortrud,et al.  Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[75]  V. Hruby,et al.  Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction. , 2000, Urology.

[76]  V. Hruby,et al.  Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. , 1998, The Journal of urology.

[77]  Katherine S Brown,et al.  Central injection in rats of α-melanocyte-stimulating hormone analog: effects on food intake and brain Fos , 1998, Regulatory Peptides.

[78]  M. I. Gonzalez,et al.  Behavioral effects of α-MSH and MCH after central administration in the female rat , 1996, Peptides.

[79]  S. Woods,et al.  Immediate and Prolonged Patterns of Agouti-Related Peptide-(83-132)-Induced c-Fos Activation in Hypothalamic and Extrahypothalamic Sites. , 2001, Endocrinology.

[80]  W. Bilecki,et al.  The effect of morphine on MC4 and CRF receptor mRNAs in the rat amygdala and attenuation of tolerance after their blockade , 2003, Brain Research.

[81]  E. J. Green,et al.  Intracerebral adrenocorticotropic hormone mediates novelty-induced grooming in the rat. , 1979, Science.

[82]  T. Pigott,et al.  A review of the efficacy of selective serotonin reuptake inhibitors in obsessive-compulsive disorder. , 1999, The Journal of clinical psychiatry.

[83]  S. Chaki,et al.  Regulation of CRF, POMC and MC4R gene expression after electrical foot shock stress in the rat amygdala and hypothalamus. , 2004, The Journal of veterinary medical science.

[84]  J. M. Lipton,et al.  Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation , 2004, Pharmacological Reviews.

[85]  J. Burbach,et al.  Expression of the pro-opiomelanocortin gene in dorsal root ganglia, spinal cord and sciatic nerve after sciatic nerve crush in the rat. , 1992, Brain research. Molecular brain research.

[86]  G. Bray,et al.  Acetylation alters the feeding response to MSH and beta-endorphin , 1989, Brain Research Bulletin.

[87]  H. Goodman,et al.  Most of the coding region of rat ACTHβ–LPH precursor gene lacks intervening sequences , 1980, Nature.

[88]  S. Sarkar,et al.  Intracerebroventricular administration of α-melanocyte stimulating hormone increases phosphorylation of CREB in TRH- and CRH-producing neurons of the hypothalamic paraventricular nucleus , 2002, Brain Research.

[89]  Z. Liposits,et al.  Neuropeptide-Y and ACTH-immunoreactive innervation of corticotropin releasing factor (CRF)-synthesizing neurons in the hypothalamus of the rat , 2004, Histochemistry.

[90]  M. Mortrud,et al.  Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. , 1994, Molecular endocrinology.

[91]  J. Wikberg,et al.  Molecular cloning of a novel human melanocortin receptor. , 1993, Biochemical and biophysical research communications.

[92]  Stanley N Cohen,et al.  Nucleotide sequence of cloned cDNA for bovine corticotropin-β-lipotropin precursor , 1979, Nature.

[93]  G. Barsh,et al.  Anatomy of an Endogenous Antagonist: Relationship between Agouti-Related Protein and Proopiomelanocortin in Brain , 1999, The Journal of Neuroscience.

[94]  W. Bilecki,et al.  Melanocortin 4 receptor is expressed in the dorsal root ganglions and down-regulated in neuropathic rats , 2004, Neuroscience Letters.

[95]  Shigeru Okuyama,et al.  Involvement of the melanocortin MC4 receptor in stress-related behavior in rodents. , 2003, European journal of pharmacology.

[96]  G. Barsh,et al.  Behavioral / Systems / Cognitive Interaction between-Melanocyte-Stimulating Hormone and Corticotropin-Releasing Hormone in the Regulation of Feeding and Hypothalamo-Pituitary-Adrenal Responses , 2003 .

[97]  G. Griebel,et al.  Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[98]  R. Cone,et al.  Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice , 1997, Cell.

[99]  W. Gispen,et al.  Antagonism of the Melanocortin System Reduces Cold and Mechanical Allodynia in Mononeuropathic Rats , 2000, The Journal of Neuroscience.

[100]  Richard P. Woychik,et al.  Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor , 1994, Nature.

[101]  A. Bertolini,et al.  ACTH-induced hyperalgesia in rats , 1979, Experientia.

[102]  Michael Davis,et al.  The Extended Amygdala: Are the Central Nucleus of the Amygdala and the Bed Nucleus of the Stria Terminalis Differentially Involved in Fear versus Anxiety? , 1999, Annals of the New York Academy of Sciences.

[103]  C. Haskell-Luevano,et al.  Agouti-related protein functions as an inverse agonist at a constitutively active brain melanocortin-4 receptor , 2001, Regulatory Peptides.

[104]  W. Vale,et al.  Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin , 1981 .

[105]  R. Seeley,et al.  A Novel Selective Melanocortin-4 Receptor Agonist Reduces Food Intake in Rats and Mice without Producing Aversive Consequences , 2000, The Journal of Neuroscience.

[106]  J. Weiel,et al.  Agouti structure and function: characterization of a potent alpha-melanocyte stimulating hormone receptor antagonist. , 1995, Biochemistry.

[107]  J. M. Lipton,et al.  Central neurogenic antiinflammatory action of alpha-MSH: modulation of peripheral inflammation induced by cytokines and other mediators of inflammation. , 1994, Neuroendocrinology.

[108]  W. Fratta,et al.  Proconflict effect of ACTH1−24: Interaction with benzodiazepines , 1990, Pharmacology Biochemistry and Behavior.

[109]  W. Gispen,et al.  Characterization of melanocortin receptor ligands on cloned brain melanocortin receptors and on grooming behavior in the rat. , 1999, European journal of pharmacology.

[110]  R. Duman,et al.  Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction. , 1996, Molecular pharmacology.

[111]  P. Plotsky,et al.  Mediation by corticotropin releasing factor (CRF) of adenohypophysial hormone secretion. , 1986, Annual review of physiology.

[112]  N. Lezcano,et al.  Alpha MSH-induced excessive grooming behavior involves a GABAergic mechanism , 1991, Peptides.