The Melanocortin System for New Antidepressant Drugs: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Igor Grivennikov.

Major depression is one of the most prevalent mental disorders, causing significant human suffering and socioeconomic loss. Since conventional antidepressants are not sufficiently effective, there is an urgent need to develop new antidepressant medications. Despite marked advances in the neurobiology of depression, the etiology and pathophysiology of this disease remain poorly understood. Classical and newer hypotheses of depression suggest that an imbalance of brain monoamines, dysregulation of the hypothalamic-pituitary-adrenal axis (HPAA) and immune system, or impaired hippocampal neurogenesis and neurotrophic factors pathways are cause of depression. It is assumed that conventional antidepressants improve these closely related disturbances.

  • melanocortins
  • depression
  • inflammation
  • hypothalamic-pituitary-adrenal axis

1. Introduction

Major depressive disorder (MDD) is one of the most common mental disorders. According to the World Health Organization, around 280 million people worldwide suffer from depression [1]. Only a small proportion of people suffering from depression use mental health services. In high-income countries, 33% of people with symptoms of depression use mental health services, and only 8% in low-income countries. Even fewer patients receive minimally adequate treatment (23% in high-income countries and 3% in low-income countries) [2].
According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), to be diagnosed with Major Depressive Disorder, a person must have at least 5 of the following 9 symptoms for at least two weeks: depressed mood, markedly diminished interest or pleasure in all or almost all activities (anhedonia), decrease or increase in appetite (weight loss or weight gain), insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate or indecisiveness, recurrent thoughts of death (suicidal ideation) [3]. The patient must necessarily have at least one core symptom: depressed mood or anhedonia. Obviously, patients with MDD will be characterized by significantly different combinations of symptoms, and two patients with the same diagnosis may have only one symptom in common [4]. Such a variety of symptoms of MDD suggests the involvement of various brain systems in the manifestation of this disease.
Despite significant advances in the study of depression in recent decades, the mechanisms of the onset and development of depression remain poorly understood. The mechanisms of the therapeutic effects of pharmacological agents used to treat depression are also obscure.
The heritability of depression is estimated at 31–42% [5,6][5][6]. Despite the identification of genetic loci thought to increase the risk of developing depression, genome-wide association studies have not led to the discovery of genes associated with the development of this mental disorder [7,8,9,10][7][8][9][10]. Transcriptome-wide association studies indicate changes in the expression of a large number of genes in depression [11,12,13][11][12][13]. But the reproducibility of both transcriptome-wide association studies and genome-wide association studies is still low. Such unsuccessful attempts to identify genes are explained by the polygenic nature of depression, when the contribution of each individual gene to the development of depression is small. Attempts are also being made to detect genes associated with the development of depression and associated with dysfunction of various physiological systems. For this purpose, gene expression is assessed in post-mortem brain samples and peripheral blood of depressed patients. Such studies have led to the discovery of potential candidate genes involved in inflammation, neuroplasticity, synaptic transmission, and HPAA regulation [14,15,16,17][14][15][16][17].
Depression is a complex heterogeneous disease that depends on a combination of genetic and environmental factors. The most influential hypotheses of depression are as follows: monoamine (assumes a decrease in monoamine levels as a cause of depression), neurotrophic (a decrease in neurotrophic factors levels, mainly BDNF), impaired neurogenesis in the hippocampus, neuroendocrine (hyperactivation of the HPAA), glutamate (altered glutamatergic excitation), and immune/inflammatory (increased levels of inflammatory cytokines) hypotheses [18,19,20,21][18][19][20][21]. Probably, all these hypotheses reflect various interrelated aspects of the pathogenesis and manifestation of depression and/or correspond to different processes leading ultimately to the onset of this disease.
Most of the current drug treatments for depression are based on the monoamine hypothesis, which considers a decrease in brain levels of monoamines as the cause of the development of depressive symptoms. First-generation antidepressants include tricyclic antidepressants and monoamine oxidase inhibitors, while better-tolerated second-generation antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and norepinephrine and dopamine reuptake inhibitors (NDRIs) [22,23][22][23]. Both first- and second-generation antidepressants have a number of adverse side effects. Among the most common undesired effects are nausea, diarrhea, weight gain, drowsiness, insomnia, dizziness, headache, and sexual dysfunction. The most dangerous side effect of antidepressants is an increased risk of suicide in depressed children and young adults [24]. Side effects of antidepressants, which are often intolerable, limit their use in clinical practice. Almost 40% of patients do not experience long-term improvement after antidepressant treatment. Such cases are referred to as a treatment-resistant depression (TRD)—the impossibility of achieving and maintaining euthymia during therapy with various types of antidepressants [25,26][25][26]. The resistance of a significant proportion of patients to antidepressants may also indicate the existence of different mechanisms underlying depression onset in different patients.
In addition to side effects and resistance to antidepressants, another significant drawback is the need for their long-term use to achieve a therapeutic effect. The effectiveness of clinically used antidepressants is also questionable [27,28][27][28]. The monoamine hypothesis of depression is firmly entrenched not only in public consciousness, but also in the scientific community and the strategies of pharmaceutical companies. However, the monoamine hypothesis is being seriously criticized, in part, due to the fact that convincing evidence indicating the involvement of serotonin in the development of depression has not been presented [29].
Because of the obvious shortcomings of antidepressants used in clinical practice, there is a need to find alternative approaches to the treatment of this mental disorder. There is an urgent need for antidepressant drugs that are effective in patients with TRD, are better tolerated by patients, and have a faster therapeutic effect. As noted above, traditional antidepressants demonstrate a delayed therapeutic effect. At the same time, the development of fast-acting antidepressants is principally possible, as evidenced by the effectiveness of sleep deprivation and the effects of low doses of ketamine [30]. In the case of ketamine, it has been shown that its administration leads to an improvement in symptoms within a few hours [31,32,33][31][32][33]. The mechanisms of the antidepressant effects of this noncompetitive NMDA receptor antagonist are still unclear. However, the recently demonstrated involvement of opioid system activation in the antidepressant effects of ketamine [34,35][34][35] not only may be related to its rapid antidepressant effects, but also raises questions about its safety in long-term use.
Peptidergic systems may be potential targets for the development of drugs for the treatment of depression. It is assumed that stress-related neuropeptides may play an important role in the development of anxiety and depression [36], while both the neuropeptides themselves and their receptors are considered as potential targets for the treatment of mental disorders [37,38,39][37][38][39].
One such system is the melanocortin system, consisting of adrenocorticotropic hormone (ACTH)-activated receptors and their ligands (melanocortins). ACTH is a key component of the body’s stress response. Melanocortin receptors mediate various effects of ACTH and related peptides in the brain and periphery. Interest in the study of the central melanocortin system was significantly stimulated by its critical involvement in the regulation of energy balance and body weight [40]. There are very close interrelationships at the functional and neuroanatomical levels between the regulation of energy balance and the neuroendocrine stress response, and this is confirmed by the high comorbidity of obesity-related pathologies and stress-related mental disorders [41]. The melanocortin system is a critical component and regulator of the neuroendocrine stress response, and its role in stress and stress-induced pathologies, such as anxiety and depression, is also being actively studied [42].

2. The Melanocortin System

The melanocortin system consists of a family of melanocortin peptides and a family of their receptors [43]. Melanocortins are a family of peptides derived from the 26 kDa proopiomelanocortin (POMC) precursor. POMC processing results in a number of bioactive peptides, including ACTH, α-melanocyte stimulating hormone (α-MSH), β-melanocyte stimulating hormone (β-MSH), γ-melanocyte stimulating hormone (γ-MSH), β-lipotropic hormone (β-LPH), and β-endorphin [44]. All melanocortins originate from different parts of proopiomelanocortin molecule by limited proteolysis. α-MSH is the N-terminal part of the ACTH molecule, β-MSH originates from beta-lipotropin, and γ-MSH peptides originate from the N-terminal sequence of proopiomelanocortin. Modifications of N-terminal amino acids (acylation) or amidation of the C-terminal alter the stability and activity of these peptides. The main source of proopiomelanocortin is the pituitary gland (its anterior and intermediate lobes), however, POMC mRNA is also found in other brain structures, as well as in peripheral organs and tissues, such as lymphocytes, skin, placenta, pancreas, thyroid gland, testes, intestine, kidneys, and liver [45]. α-MSH in the rat brain is also characterized by a scattered distribution. Its highest content was found in the neurons of the arcuate nucleus of the hypothalamus. α-MSH was not found in the cerebral cortex and cerebellum [46]. The physiological effects of melanocortins are mediated through their interaction with melanocortin receptors (MCRs). Cloning of the MCR genes has led to tremendous progress in understanding the biological role of melanocortins. Five subtypes of MCRs have been identified (MC1R, MC2R, MC3R, MC4R, MC5R) [47]. MCRs are classic G-protein coupled receptors with seven transmembrane domains. MCRs have 40–60% amino acid sequence homology, and they differ in their tissue distribution and affinity for various melanocortins and physiological antagonists, such as ASIP (agouti-signaling protein) and AGRP (agouti-related protein) [47,48][47][48]. ACTH, a peptide of 39 amino acids residues, and its N-terminal fragments longer than 1–16 activate all five MCR subtypes. α-MSH activates four subtypes (MC1R, MC3R, MC4R, MC5R), however shorter α-MSH fragments are not able to activate MC1R but still can activate other subtypes of MCRs [49]. The expression of MC3R, MC4R, and MC5R subtypes has been found in the brain [49,50][49][50]. By binding to the corresponding receptor, melanocortins are able to activate a number of signaling cascades, such as: AC/cAMP/PKA, PLCβ/DAG/PKC, PLCβ/IP3/Ca2+, Jak/STAT, PI3K/ERK1/2 [51]. The specific effect exerted by MCR agonists depends on the subtype of the activated receptor and its tissue localization. MC1R is responsible for skin and hair pigmentation, MC2R is required for steroidogenesis in the adrenal cortex, MC3R and MC4R are involved in the control of food intake and behavior, and MC5R plays an important role in sebogenesis [43]. The accessory proteins of the MCRs (MRAP and MRAP2) are also important. These proteins interact with all five MCRs, are involved in the trafficking of receptors from the endoplasmic reticulum to the plasma membrane, modulate their activity upon binding to ligands, and are involved in the internalization of receptors [52,53][52][53]. Mutations in the genes of MCRs and accessory proteins can lead to the development of a number of diseases. Mutations in the MC1R gene are associated with an increased risk of melanoma, MC2R mutations result in familial glucocorticoid deficiency, and mutations in the MC4R and MRAP2 genes are associated with severe forms of obesity [54]. As there is both a wide variety of functions are carried out by the activation of melanocortin receptors, and there are many diseases associated with mutations in the genes of these receptors, they have become attractive targets for drug development. In addition to endogenous melanocortins, a large number of their analogs have been synthesized [55]. Currently, several melanocortin-based drugs have already been approved for clinical use: Acthar® Gel—full-length ACTH1-39 (treatment of multiple sclerosis and infantile spasms), CortrosynTM—an ACTH1-24 fragment (used to diagnose adrenal insufficiency), Synacthen ®Depot—a fragment of ACTH1-24 (treatment of multiple sclerosis, rheumatoid diseases, ulcerative colitis, nephrotic syndrome, and as a diagnostic test for adrenal insufficiency), Scenesse®—Afamelanotide, an α-MSH analogue (treatment of erythropoietic protoporphyria), Vyleesi®—Bremelanotide, a cyclic heptapeptide (treatment of hypoactive sexual desire disorder in women), and Imcivree ®—Setmelanotide, a cyclic octapeptide (treatment of monogenic or syndromic obesity) [56].

3. The Effect of Melanocortins on Depression-like and Anxious Behavior

The question of the endogenous level of melanocortins in depression remains open due to the small number of studies on this topic. Some researchers indicate a reduced plasma level of α-MSH in MDD patients [300][57], other authors do not detect any differences in the plasma level of α-MSH between MDD patients and healthy controls [301][58]. There were no differences between depressed patients and healthy controls in α-MSH and ACTH levels in cerebrospinal fluid and plasma [302][59]. There are currently no data on the effect of melanocortins on depressive and anxious behavior in humans. The only exception is a study, which showed that IV administration of an ACTH/MSH4-10 to human subjects leads to a decrease in anxiety [303][60]. Sequence polymorphisms of MCR genes may contribute to the risk of major depressive disorder. It has been shown that the rs885479 polymorphism in the MC1R gene [304][61], rs111734014 polymorphism in the MC2R gene, and rs2236700 in the MC5R gene are associated with the risk of MDD [305][62]. Indirectly, the possible involvement of the melanocortin system in depression is indicated by studies demonstrating a close relationship between depression and obesity [306,307][63][64]. A change in appetite (and consequently a change in body weight) is one of the symptoms of depression. In turn, melanocortins are important regulators of feeding behavior [308,309,310,311][65][66][67][68]. The role of melanocortins in animal models of anxiety and depression is being actively studied. Central endogenous α-MSH may be involved in the development of anxiety and depression. Most studies point to the antidepressant and anxiolytic properties of melanocortin receptor antagonists and the anxiogenic effects of agonists. Antidepressant and anxiolytic properties are exerted by central and peripheral administration of selective MC4R antagonists, such as HS014 [312][69], MCL0129 [313][70], MCL0042 [314][71], and the MC3R/MC4R antagonist SHU 9119 [315,316][72][73]. Intranasal infusion of HS014 also prevents development of depressive-like and anxiety-like behavior [317,318][74][75]. The important role of MC4R allows for it to be considered as a target for the development of drugs for the treatment of stress-associated diseases, such as anxiety and depression [319][76]. Centrally administered MCRs agonists exert anxiogenic effects. The level of anxiety increases after central administration of α-MSH [320,321][77][78] and ACTH1-24 [322][79], but not of ACTH4-10 and ACTH11-24. Similar effects have been observed after α-MSH administration into the medial preoptic area [323][80]. MC4R signaling in the dorsal raphe nucleus affects anxiety and depression-like behavior [324][81]. However, centrally administered melanocortins may exert quite the opposite effects antagonizing the action of cytokines. Central administration of α-MSH reverses IL-1β-induced anxiety and administration of HS014 inhibit the effect of α-MSH [325][82]. The effects of melanocortin receptor agonists on depression-like behavior are even more controversial. Some authors point to the prodepressant properties of α-MSH after central administration [326][83], while others do not demonstrate any influence of α-MSH on the depression-like behavior [327][84]. Peripherally administered melanocortins exert antidepressant effects. IP administration of α-MSH (but not ACTH4-10 and ACTH1-24) decrease immobility in the forced swim test [328][85]. IP administered ACTH6-9-Pro-Gly-Pro also exerts antidepressant and anxiolytic effects [329][86]. Several studies have shown that chronic administration of ACTH blocks the effects of antidepressants. A single administration of either imipramine or desipramine significantly decreases the duration of immobility in normal rats. The immobility-decreasing effect induced by a single administration of antidepressants is blocked by chronic administration of ACTH1-24, which like a full-sized ACTH, possesses corticotropic activity [331,332,333][87][88][89]. Antidepressants can also affect the melanocortin system. Fluoxetine administration increases POMC expression and reduces MC4R expression in the hypothalamus [334][90]. POMC mRNA levels in the arcuate nucleus of the hypothalamus are increased following chronic treatment with phenelzine and idazoxan [335][91]. However, orally administered fluoxetine decrease α-MSH levels in the PVN of the hypothalamus [336][92]. The above data indicate the involvement of the melanocortin system in the development of depressive-like and anxious behavior. The inconsistency of these data indicates the need for further research in this area. The effects of agonists and antagonists of melanocortin receptors depend on the route of administration (central or peripheral), the ability of drugs to cross the blood-brain barrier, the specific area into which the drug is administered when it is administered centrally, and the dose and selectivity of the agonist/antagonist to MCRs.

4. The Role of Melanocortins in Motivational and Hedonic Behavior

Melanocortins are involved in the regulation of feeding behavior. Central administration of melanocortin receptor agonists decrease food intake. Melanocortins are able to regulate not only homeostatic (metabolic), but also motivational and hedonic aspects of feeding behavior, which is of particular interest from the point of view of anhedonia. Anhedonia is most often assessed by the sucrose preference test in experimental models. MC4R deficient individuals exhibit a significantly reduced preference for high sucrose food [337][93]. Deletion of both alleles of the MC4R decreases preference for palatable high-sucrose foods in wild-type mice [338][94]. Global deletion of the MC3R decreases sucrose intake and preference in female but not male mice [339][95]. The importance of the melanocortin system in the regulation of the motivational and consummatory phases of food consumption is evidenced by animal studies using melanocortin receptor agonists and antagonists. MT-II injected into the NAc decrease both appetitive (motivational) and consummatory feeding behavior in mice [340][96]. Chronic stress-elicited anhedonia requires activation of MC4R in the NAc [293][97]. Injection of MT-II into the VTA decreases motivation to obtain sucrose pellets on both fixed ratio and progressive ratio schedules of reinforcement [341][98] and decreases the intake of sucrose solution [342][99]. Intra-VTA infusion of the selective MC3R agonist γ-MSH, on the contrary, increases responding for sucrose under a progressive ratio schedule of reinforcement [343][100]. MC4R in the dorsomedial striatum appears to propel reward-seeking behavior [344][101]. Food motivated behavior tested under a progressive ratio schedule of reinforcement dose-dependently decreased by ICV-injected α-MSH. In contrast to progressive ratio responding, free intake of sucrose remains unaltered upon α-MSH infusion. The authors suggest that the motivation for palatable food is modulated by MC4R in the NAc [345][102]. Central AGRP administration results in significantly increased motivation for sucrose solution in rats under a progressive ratio schedule of reinforcement [346][103]. Chronic central MCR ligand infusion (SHU 9119 and MT-II) does not affect the response to non-ingestive reward stimuli (lateral hypothalamic electrical stimulation) [347][104]. However, ICV infusion of α-MSH decreases the rewarding properties of social interactions (rewarding stimulus) in Syrian hamsters [348][105]. The effect of melanocortins on the perception of aversive stimuli was also shown. In normal mice, systemic inflammation induced by LPS administration, results in aversion in a conditioned place aversion paradigm. In contrast, mice lacking MC4R display preference toward the aversive stimuli. Intranasal administration of MC4R antagonist HS014 prior to LPS injection to wild-type mice results in antiaversive effect. This means that MC4R signaling is required for assigning negative motivational valence to aversive stimuli [349][106]. The mechanisms of the regulatory effects of melanocortins on the motivational and hedonic aspects of feeding behavior are currently unknown. The interaction of the melanocortin and dopaminergic systems can play an important role. Hyperactivity of POMC neurons in the arcuate nucleus of the hypothalamus (POMCARH neurons) results in decreased neural activities of dopamine neurons in the VTA. Inhibition of the POMCARH→VTA circuit reduces depression-like behavior and anhedonia in mice exposed to chronic restraint stress [350][107]. α-MSH infusion into the lateral hypothalamic area decreases food intake and sucrose consumption and increases dopamine levels in rats. Dopamine release occurs in both the anticipatory and consummatory phases of feeding. These data suggest that α-MSH-stimulated activation of the dopaminergic system is involved in homeostatic and hedonic satiation [351][108]. These data indicate the involvement of central melanocortin receptors in the regulatory mechanisms of the motivational and hedonic aspects of feeding behavior, and the close relationship between the melanocortin and dopaminergic systems. Virtually all studies point to the ability of melanocortin receptor agonists, after their central administration, to suppress motivation for food rewards and reduce the consumption/preference for palatable food. However, nothing is known about the effects of melanocortins after their peripheral administration in this context.

5. Some Features of Melanocortins and Their Possible Site of Action

Melanocortins are often injected ICV or directly into those brain structures that are of interest in a particular study. The central route of administration is unacceptable for humans and preference is given to peripheral routes of administration. But the peripheral route of administration for peptides also has limitations due to their rapid degradation by peptidases. The half-life of α-MSH in plasma is about 7–18 min and depends on the acetylation status of the peptide [352][109]. However, peptides have a number of important advantages, including high affinity, specificity for receptors, as well as low immunogenicity and toxicity. There are approaches that improve the absorption properties of peptides, increase their proteolytic stability, and reduce renal clearance. Among the strategies that are often used in the creation of drugs based on peptides are: molecule cyclization, N-terminus acetylation, replacement of L-amino acids with D-amino acids, the use of non-canonical amino acids, and conjugation to other molecules [353,354][110][111]. The nature of the effects after the peripheral administration of melanocortins indicates their central action, but α-MSH does not cross the blood-brain barrier [355][112]. How melanocortins exert central effects after peripheral administration remains unknown. Circumventricular organs may play an important role in this process. Melanocortins [356][113] and their binding sites [357,358,359][114][115][116] were found in the median eminence. Probably, different members of the melanocortin family differ in their ability to cross the blood-brain barrier. A synthetic analogue of melanocortins (Semax) penetrates into the brain both after IV [360][117] and after intranasal administration [361][118]. In contrast, MT-II, a synthetic analog of α-MSH, does not cross the blood-brain barrier after IV administration and is detectable only in circumventricular organs [362][119]. It is possible that small-molecules agonists and antagonists of melanocortin receptors will be able to cross the blood-brain barrier much more easily.

References

  1. World Health Organization. Depression. 2023. Available online: https://www.who.int/news-room/fact-sheets/detail/depression (accessed on 28 February 2023).
  2. Moitra, M.; Santomauro, D.; Collins, P.Y.; Vos, T.; Whiteford, H.; Saxena, S.; Ferrari, A.J. The Global Gap in Treatment Coverage for Major Depressive Disorder in 84 Countries from 2000–2019: A Systematic Review and Bayesian Meta-Regression Analysis. PLoS Med. 2022, 19, e1003901.
  3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association: Washington, DC, USA, 2013; ISBN 0-89042-555-8.
  4. van Loo, H.M.; de Jonge, P.; Romeijn, J.-W.; Kessler, R.C.; Schoevers, R.A. Data-Driven Subtypes of Major Depressive Disorder: A Systematic Review. BMC Med. 2012, 10, 156.
  5. Sullivan, P.F.; Neale, M.C.; Kendler, K.S. Genetic Epidemiology of Major Depression: Review and Meta-Analysis. Am. J. Psychiatry 2000, 157, 1552–1562.
  6. Kendler, K.S.; Gatz, M.; Gardner, C.O.; Pedersen, N.L. A Swedish National Twin Study of Lifetime Major Depression. Am. J. Psychiatry 2006, 163, 109–114.
  7. Ripke, S.; Wray, N.R.; Lewis, C.M.; Hamilton, S.P.; Weissman, M.M.; Breen, G.; Byrne, E.M.; Blackwood, D.H.R.; Boomsma, D.I.; Cichon, S.; et al. A Mega-Analysis of Genome-Wide Association Studies for Major Depressive Disorder. Mol. Psychiatry 2013, 18, 497–511.
  8. Wray, N.R.; Ripke, S.; Mattheisen, M.; Trzaskowski, M.; Byrne, E.M.; Abdellaoui, A.; Adams, M.J.; Agerbo, E.; Air, T.M.; Andlauer, T.M.F.; et al. Genome-Wide Association Analyses Identify 44 Risk Variants and Refine the Genetic Architecture of Major Depression. Nat. Genet. 2018, 50, 668–681.
  9. Howard, D.M.; Adams, M.J.; Clarke, T.-K.; Hafferty, J.D.; Gibson, J.; Shirali, M.; Coleman, J.R.I.; Hagenaars, S.P.; Ward, J.; Wigmore, E.M.; et al. Genome-Wide Meta-Analysis of Depression Identifies 102 Independent Variants and Highlights the Importance of the Prefrontal Brain Regions. Nat. Neurosci. 2019, 22, 343–352.
  10. Flint, J. The Genetic Basis of Major Depressive Disorder. Mol. Psychiatry 2023.
  11. Dall’Aglio, L.; Lewis, C.M.; Pain, O. Delineating the Genetic Component of Gene Expression in Major Depression. Biol. Psychiatry 2021, 89, 627–636.
  12. Fabbri, C.; Pain, O.; Hagenaars, S.P.; Lewis, C.M.; Serretti, A. Transcriptome-Wide Association Study of Treatment-Resistant Depression and Depression Subtypes for Drug Repurposing. Neuropsychopharmacology 2021, 46, 1821–1829.
  13. Li, X.; Su, X.; Liu, J.; Li, H.; Li, M.; Li, W.; Luo, X.-J. Transcriptome-Wide Association Study Identifies New Susceptibility Genes and Pathways for Depression. Transl. Psychiatry 2021, 11, 306.
  14. Mariani, N.; Cattane, N.; Pariante, C.; Cattaneo, A. Gene Expression Studies in Depression Development and Treatment: An Overview of the Underlying Molecular Mechanisms and Biological Processes to Identify Biomarkers. Transl. Psychiatry 2021, 11, 354.
  15. Morrison, F.G.; Miller, M.W.; Wolf, E.J.; Logue, M.W.; Maniates, H.; Kwasnik, D.; Cherry, J.D.; Svirsky, S.; Restaino, A.; Hildebrandt, A.; et al. Reduced Interleukin 1A Gene Expression in the Dorsolateral Prefrontal Cortex of Individuals with PTSD and Depression. Neurosci. Lett. 2019, 692, 204–209.
  16. Leday, G.G.R.; Vértes, P.E.; Richardson, S.; Greene, J.R.; Regan, T.; Khan, S.; Henderson, R.; Freeman, T.C.; Pariante, C.M.; Harrison, N.A.; et al. Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder. Biol. Psychiatry 2018, 83, 70–80.
  17. Cattaneo, A.; Ferrari, C.; Turner, L.; Mariani, N.; Enache, D.; Hastings, C.; Kose, M.; Lombardo, G.; McLaughlin, A.P.; Nettis, M.A.; et al. Whole-Blood Expression of Inflammasome- and Glucocorticoid-Related MRNAs Correctly Separates Treatment-Resistant Depressed Patients from Drug-Free and Responsive Patients in the BIODEP Study. Transl. Psychiatry 2020, 10, 232.
  18. Krishnan, V.; Nestler, E.J. The Molecular Neurobiology of Depression. Nature 2008, 455, 894–902.
  19. Li, Z.; Ruan, M.; Chen, J.; Fang, Y. Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications. Neurosci. Bull. 2021, 37, 863–880.
  20. Kamran, M.; Bibi, F.; ur Rehman, A.; Morris, D.W. Major Depressive Disorder: Existing Hypotheses about Pathophysiological Mechanisms and New Genetic Findings. Genes 2022, 13, 646.
  21. Lv, S.; Yao, K.; Zhang, Y.; Zhu, S. NMDA Receptors as Therapeutic Targets for Depression Treatment: Evidence from Clinical to Basic Research. Neuropharmacology 2023, 225, 109378.
  22. Sheffler, Z.M.; Patel, P.; Abdijadid, S. Antidepressants; StatPearls Publishing: Treasure Island, FL, USA, 2022.
  23. Tian, H.; Hu, Z.; Xu, J.; Wang, C. The Molecular Pathophysiology of Depression and the New Therapeutics. MedComm 2022, 3.
  24. Li, K.; Zhou, G.; Xiao, Y.; Gu, J.; Chen, Q.; Xie, S.; Wu, J. Risk of Suicidal Behaviors and Antidepressant Exposure Among Children and Adolescents: A Meta-Analysis of Observational Studies. Front. Psychiatry 2022, 13, 880496.
  25. Fava, M.; Davidson, K.G. Definition and epidemiology of treatment-resistant depression. Psychiatr. Clin. N. Am. 1996, 19, 179–200.
  26. Schroder, H.S.; Patterson, E.H.; Hirshbein, L. Treatment-Resistant Depression Reconsidered. SSM–Ment. Health 2022, 2, 100081.
  27. Kirsch, I.; Deacon, B.J.; Huedo-Medina, T.B.; Scoboria, A.; Moore, T.J.; Johnson, B.T. Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLoS Med. 2008, 5, e45.
  28. Hengartner, M.P.; Jakobsen, J.C.; Sørensen, A.; Plöderl, M. Efficacy of New-Generation Antidepressants Assessed with the Montgomery-Asberg Depression Rating Scale, the Gold Standard Clinician Rating Scale: A Meta-Analysis of Randomised Placebo-Controlled Trials. PLoS ONE 2020, 15, e0229381.
  29. Moncrieff, J.; Cooper, R.E.; Stockmann, T.; Amendola, S.; Hengartner, M.P.; Horowitz, M.A. The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence. Mol. Psychiatry 2022.
  30. Machado-Vieira, R.; Baumann, J.; Wheeler-Castillo, C.; Latov, D.; Henter, I.; Salvadore, G.; Zarate, C. The Timing of Antidepressant Effects: A Comparison of Diverse Pharmacological and Somatic Treatments. Pharmaceuticals 2010, 3, 19–41.
  31. Berman, R.M.; Cappiello, A.; Anand, A.; Oren, D.A.; Heninger, G.R.; Charney, D.S.; Krystal, J.H. Antidepressant Effects of Ketamine in Depressed Patients. Biol. Psychiatry 2000, 47, 351–354.
  32. aan het Rot, M.; Zarate, C.A.; Charney, D.S.; Mathew, S.J. Ketamine for Depression: Where Do We Go from Here? Biol. Psychiatry 2012, 72, 537–547.
  33. Yavi, M.; Lee, H.; Henter, I.D.; Park, L.T.; Zarate, C.A. Ketamine Treatment for Depression: A Review. Discov. Ment. Health 2022, 2, 9.
  34. Williams, N.R.; Heifets, B.D.; Blasey, C.; Sudheimer, K.; Pannu, J.; Pankow, H.; Hawkins, J.; Birnbaum, J.; Lyons, D.M.; Rodriguez, C.I.; et al. Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. Am. J. Psychiatry 2018, 175, 1205–1215.
  35. Zhang, F.; Hillhouse, T.M.; Anderson, P.M.; Koppenhaver, P.O.; Kegen, T.N.; Manicka, S.G.; Lane, J.T.; Pottanat, E.; Van Fossen, M.; Rice, R.; et al. Opioid Receptor System Contributes to the Acute and Sustained Antidepressant-like Effects, but Not the Hyperactivity Motor Effects of Ketamine in Mice. Pharmacol. Biochem. Behav. 2021, 208, 173228.
  36. Alldredge, B. Pathogenic Involvement of Neuropeptides in Anxiety and Depression. Neuropeptides 2010, 44, 215–224.
  37. Holmes, A.; Heilig, M.; Rupniak, N.M.J.; Steckler, T.; Griebel, G. Neuropeptide Systems as Novel Therapeutic Targets for Depression and Anxiety Disorders. Trends Pharmacol. Sci. 2003, 24, 580–588.
  38. Kormos, V.; Gaszner, B. Role of Neuropeptides in Anxiety, Stress, and Depression: From Animals to Humans. Neuropeptides 2013, 47, 401–419.
  39. Kupcova, I.; Danisovic, L.; Grgac, I.; Harsanyi, S. Anxiety and Depression: What Do We Know of Neuropeptides? Behav. Sci. 2022, 12, 262.
  40. Lee, M. The Central Melanocortin System and the Regulation of Energy Balance. Front. Biosci. 2007, 12, 3994.
  41. Ulrich-Lai, Y.M.; Ryan, K.K. Neuroendocrine Circuits Governing Energy Balance and Stress Regulation: Functional Overlap and Therapeutic Implications. Cell Metab. 2014, 19, 910–925.
  42. Micioni Di Bonaventura, E.; Botticelli, L.; Del Bello, F.; Giorgioni, G.; Piergentili, A.; Quaglia, W.; Romano, A.; Gaetani, S.; Micioni Di Bonaventura, M.V.; Cifani, C. Investigating the Role of the Central Melanocortin System in Stress and Stress-Related Disorders. Pharmacol. Res. 2022, 185, 106521.
  43. Laiho, L.; Murray, J.F. The Multifaceted Melanocortin Receptors. Endocrinology 2022, 163, bqac083.
  44. Harno, E.; Gali Ramamoorthy, T.; Coll, A.P.; White, A. POMC: The Physiological Power of Hormone Processing. Physiol. Rev. 2018, 98, 2381–2430.
  45. Smith, A.I.; Funder, J.W. Proopiomelanocortin Processing in the Pituitary, Central Nervous System, and Peripheral Tissues. Endocr. Rev. 1988, 9, 159–179.
  46. Jacobowitz, D.M.; O’Donohue, T.L. Alpha-Melanocyte Stimulating Hormone: Immunohistochemical Identification and Mapping in Neurons of Rat Brain. Proc. Natl. Acad. Sci. USA 1978, 75, 6300–6304.
  47. Wikberg, J.E. Melanocortin Receptors: Perspectives for Novel Drugs. Eur. J. Pharmacol. 1999, 375, 295–310.
  48. Yang, Y. Structure, Function and Regulation of the Melanocortin Receptors. Eur. J. Pharmacol. 2011, 660, 125–130.
  49. Getting, S.J. Targeting Melanocortin Receptors as Potential Novel Therapeutics. Pharmacol. Ther. 2006, 111, 1–15.
  50. Shukla, C.; Koch, L.G.; Britton, S.L.; Cai, M.; Hruby, V.J.; Bednarek, M.; Novak, C.M. Contribution of Regional Brain Melanocortin Receptor Subtypes to Elevated Activity Energy Expenditure in Lean, Active Rats. Neuroscience 2015, 310, 252–267.
  51. Rodrigues, A.R.; Almeida, H.; Gouveia, A.M. Intracellular Signaling Mechanisms of the Melanocortin Receptors: Current State of the Art. Cell Mol. Life Sci. 2015, 72, 1331–1345.
  52. Chan, L.F.; Webb, T.R.; Chung, T.-T.; Meimaridou, E.; Cooray, S.N.; Guasti, L.; Chapple, J.P.; Egertová, M.; Elphick, M.R.; Cheetham, M.E.; et al. MRAP and MRAP2 Are Bidirectional Regulators of the Melanocortin Receptor Family. Proc. Natl. Acad. Sci. USA 2009, 106, 6146–6151.
  53. Berruien, N.N.A.; Smith, C.L. Emerging Roles of Melanocortin Receptor Accessory Proteins (MRAP and MRAP2) in Physiology and Pathophysiology. Gene 2020, 757, 144949.
  54. Novoselova, T.V.; Chan, L.F.; Clark, A.J.L. Pathophysiology of Melanocortin Receptors and Their Accessory Proteins. Best Pract. Res. Clin. Endocrinol. Metab. 2018, 32, 93–106.
  55. Ericson, M.D.; Lensing, C.J.; Fleming, K.A.; Schlasner, K.N.; Doering, S.R.; Haskell-Luevano, C. Bench-Top to Clinical Therapies: A Review of Melanocortin Ligands from 1954 to 2016. Biochim. Biophys. Acta–Mol. Basis Dis. 2017, 1863, 2414–2435.
  56. Montero-Melendez, T.; Boesen, T.; Jonassen, T.E.N. Translational Advances of Melanocortin Drugs: Integrating Biology, Chemistry and Genetics. Semin. Immunol. 2022, 59, 101603.
  57. Maes, M.; DeJonckheere, C.; Vandervorst, C.; Schotte, C.; Cosyns, P.; Raus, J.; Suy, E. Abnormal Pituitary Function during Melancholia: Reduced α-Melanocyte-Stimulating Hormone Secretion and Increased Intact ACTH Non-Suppression. J. Affect. Disord. 1991, 22, 149–157.
  58. Hidese, S.; Yoshida, F.; Ishida, I.; Matsuo, J.; Hattori, K.; Kunugi, H. Plasma Neuropeptide Levels in Patients with Schizophrenia, Bipolar Disorder, or Major Depressive Disorder and Healthy Controls: A Multiplex Immunoassay Study. Neuropsychopharmacol. Rep. 2022, 43, 57–68.
  59. Berrettini, W.H.; Nurnberger, J.I.; Chan, J.S.D.; Chrousos, G.P.; Gaspar, L.; Gold, P.W.; Seidah, N.G.; Simmons-Alling, S.; Goldin, L.R.; Chrétien, M.; et al. Pro-Opiomelanocortin-Related Peptides in Cerebrospinal Fluid: A Study of Manic-Depressive Disorder. Psychiatry Res. 1985, 16, 287–302.
  60. Sandman, C. Enhancement of Attention in Man with ACTH/MSH 4–10. Physiol. Behav. 1975, 15, 427–431.
  61. Wu, G.-S.; Luo, H.-R.; Dong, C.; Mastronardi, C.; Licinio, J.; Wong, M.-L. Sequence Polymorphisms of MC1R Gene and Their Association with Depression and Antidepressant Response. Psychiatr. Genet. 2011, 21, 14–18.
  62. Amin, M.; Ott, J.; Wu, R.; Postolache, T.T.; Gragnoli, C. Implication of Melanocortin Receptor Genes in the Familial Comorbidity of Type 2 Diabetes and Depression. Int. J. Mol. Sci. 2022, 23, 8350.
  63. Milaneschi, Y.; Simmons, W.K.; van Rossum, E.F.C.; Penninx, B.W. Depression and Obesity: Evidence of Shared Biological Mechanisms. Mol. Psychiatry 2019, 24, 18–33.
  64. Fulton, S.; Décarie-Spain, L.; Fioramonti, X.; Guiard, B.; Nakajima, S. The Menace of Obesity to Depression and Anxiety Prevalence. Trends Endocrinol. Metab. 2022, 33, 18–35.
  65. Baldini, G.; Phelan, K.D. The Melanocortin Pathway and Control of Appetite-Progress and Therapeutic Implications. J. Endocrinol. 2019, 241, R1–R33.
  66. Kühnen, P.; Krude, H.; Biebermann, H. Melanocortin-4 Receptor Signalling: Importance for Weight Regulation and Obesity Treatment. Trends Mol. Med. 2019, 25, 136–148.
  67. Yang, Y.; Xu, Y. The Central Melanocortin System and Human Obesity. J. Mol. Cell Biol. 2020, 12, 785–797.
  68. Yeo, G.S.H.; Chao, D.H.M.; Siegert, A.-M.; Koerperich, Z.M.; Ericson, M.D.; Simonds, S.E.; Larson, C.M.; Luquet, S.; Clarke, I.; Sharma, S.; et al. The Melanocortin Pathway and Energy Homeostasis: From Discovery to Obesity Therapy. Mol. Metab. 2021, 48, 101206.
  69. Kokare, D.M.; Dandekar, M.P.; Singru, P.S.; Gupta, G.L.; Subhedar, N.K. Involvement of α-MSH in the Social Isolation Induced Anxiety- and Depression-like Behaviors in Rat. Neuropharmacology 2010, 58, 1009–1018.
  70. Chaki, S.; Hirota, S.; Funakoshi, T.; Suzuki, Y.; Suetake, S.; Okubo, T.; Ishii, T.; Nakazato, A.; Okuyama, S. Anxiolytic-Like and Antidepressant-Like Activities of MCL0129 (1--4-Piperazine), a Novel and Potent Nonpeptide Antagonist of the Melanocortin-4 Receptor. J. Pharmacol. Exp. Ther. 2003, 304, 818–826.
  71. Chaki, S.; Oshida, Y.; Ogawa, S.; Funakoshi, T.; Shimazaki, T.; Okubo, T.; Nakazato, A.; Okuyama, S. MCL0042: A Nonpeptidic MC4 Receptor Antagonist and Serotonin Reuptake Inhibitor with Anxiolytic- and Antidepressant-like Activity. Pharmacol. Biochem. Behav. 2005, 82, 621–626.
  72. Liu, J.; Garza, J.C.; Truong, H.V.; Henschel, J.; Zhang, W.; Lu, X.-Y. The Melanocortinergic Pathway Is Rapidly Recruited by Emotional Stress and Contributes to Stress-Induced Anorexia and Anxiety-Like Behavior. Endocrinology 2007, 148, 5531–5540.
  73. Liu, J.; Garza, J.C.; Li, W.; Lu, X.-Y. Melanocortin-4 Receptor in the Medial Amygdala Regulates Emotional Stress-Induced Anxiety-like Behaviour, Anorexia and Corticosterone Secretion. Int. J. Neuropsychopharmacol. 2013, 16, 105–120.
  74. Serova, L.I.; Laukova, M.; Alaluf, L.G.; Sabban, E.L. Intranasal Infusion of Melanocortin Receptor Four (MC4R) Antagonist to Rats Ameliorates Development of Depression and Anxiety Related Symptoms Induced by Single Prolonged Stress. Behav. Brain Res. 2013, 250, 139–147.
  75. Sabban, E.L.; Serova, L.I.; Alaluf, L.G.; Laukova, M.; Peddu, C. Comparative Effects of Intranasal Neuropeptide Y and HS014 in Preventing Anxiety and Depressive-like Behavior Elicited by Single Prolonged Stress. Behav. Brain Res. 2015, 295, 9–16.
  76. Chaki, S.; Okuyama, S. Involvement of Melanocortin-4 Receptor in Anxiety and Depression. Peptides 2005, 26, 1952–1964.
  77. Chaki, S.; Ogawa, S.; Toda, Y.; Funakoshi, T.; Okuyama, S. Involvement of the Melanocortin MC4 Receptor in Stress-Related Behavior in Rodents. Eur. J. Pharmacol. 2003, 474, 95–101.
  78. Kokare, D.M.; Chopde, C.T.; Subhedar, N.K. Participation of α-Melanocyte Stimulating Hormone in Ethanol-Induced Anxiolysis and Withdrawal Anxiety in Rats. Neuropharmacology 2006, 51, 536–545.
  79. Corda, M.G.; Orlandi, M.; Fratta, W. Proconflict Effect of ACTH1−24: Interaction with Benzodiazepines. Pharmacol. Biochem. Behav. 1990, 36, 631–634.
  80. Gonzalez, M.I.; Vaziri, S.; Wilson, C.A. Behavioral Effects of α-MSH and MCH after Central Administration in the Female Rat. Peptides 1996, 17, 171–177.
  81. Bruschetta, G.; Jin, S.; Liu, Z.-W.; Kim, J.D.; Diano, S. MC4R Signaling in Dorsal Raphe Nucleus Controls Feeding, Anxiety, and Depression. Cell Rep. 2020, 33, 108267.
  82. Cragnolini, A.B.; Schiöth, H.B.; Scimonelli, T.N. Anxiety-like Behavior Induced by IL-1β Is Modulated by α-MSH through Central Melanocortin-4 Receptors. Peptides 2006, 27, 1451–1456.
  83. Goyal, S.; Kokare, D.; Chopde, C.; Subhedar, N. Alpha-Melanocyte Stimulating Hormone Antagonizes Antidepressant-like Effect of Neuropeptide Y in Porsolt’s Test in Rats. Pharmacol. Biochem. Behav. 2006, 85, 369–377.
  84. Deak, T.; Bellamy, C.; D’Agostino, L.G.; Rosanoff, M.; McElderry, N.K.; Bordner, K.A. Behavioral Responses during the Forced Swim Test Are Not Affected by Anti-Inflammatory Agents or Acute Illness Induced by Lipopolysaccharide. Behav. Brain Res. 2005, 160, 125–134.
  85. Kastin, A.J.; Scollan, E.L.; Ehrensing, R.H.; Schally, A.V.; Coy, D.H. Enkephalin and Other Peptides Reduce Passiveness. Pharmacol. Biochem. Behav. 1978, 9, 515–519.
  86. Vorvul, A.O.; Bobyntsev, I.I.; Medvedeva, O.A.; Mukhina, A.Y.; Svishcheva, M.V.; Azarova, I.E.; Andreeva, L.A.; Myasoedov, N.F. ACTH(6-9)-Pro-Gly-Pro Ameliorates Anxiety-like and Depressive-like Behaviour and Gut Mucosal Microbiota Composition in Rats under Conditions of Chronic Restraint Stress. Neuropeptides 2022, 93, 102247.
  87. Kitamura, Y.; Araki, H.; Gomita, Y. Influence of ACTH on the Effects of Imipramine, Desipramine and Lithium on Duration of Immobility of Rats in the Forced Swim Test. Pharmacol. Biochem. Behav. 2002, 71, 63–69.
  88. Kitamura, Y.; Akiyama, K.; Kitagawa, K.; Shibata, K.; Kawasaki, H.; Suemaru, K.; Araki, H.; Sendo, T.; Gomita, Y. Chronic Coadministration of Carbamazepine Together with Imipramine Produces Antidepressant-like Effects in an ACTH-Induced Animal Model of Treatment–Resistant Depression: Involvement of 5-HT2A Receptors? Pharmacol. Biochem. Behav. 2008, 89, 235–240.
  89. Walker, A.J.; Burnett, S.A.; Hasebe, K.; McGillivray, J.A.; Gray, L.J.; McGee, S.L.; Walder, K.; Berk, M.; Tye, S.J. Chronic Adrenocorticotrophic Hormone Treatment Alters Tricyclic Antidepressant Efficacy and Prefrontal Monoamine Tissue Levels. Behav. Brain Res. 2013, 242, 76–83.
  90. Churruca, I.; Portillo, M.P.; Casis, L.; Gutiérrez, A.; Macarulla, M.T.; Echevarría, E. Effects of Fluoxetine Administration on Hypothalamic Melanocortin System in Obese Zucker Rats. Neuropeptides 2008, 42, 293–299.
  91. Baker, R.A.; Herkenham, M.; Brady, L.S. Effects of Long-Term Treatment with Antidepressant Drugs on Proopiomelanocortin and Neuropeptide Y MRNA Expression in the Hypothalamic Arcuate Nucleus of Rats. J. Neuroendocrinol. 1996, 8, 337–343.
  92. Ortuño, M.J.; Schneeberger, M.; Ilanges, A.; Marchildon, F.; Pellegrino, K.; Friedman, J.M.; Ducy, P. Melanocortin 4 Receptor Stimulation Prevents Antidepressant-Associated Weight Gain in Mice Caused by Long-Term Fluoxetine Exposure. J. Clin. Investig. 2021, 131, e151976.
  93. van der Klaauw, A.A.; Keogh, J.M.; Henning, E.; Stephenson, C.; Kelway, S.; Trowse, V.M.; Subramanian, N.; O’Rahilly, S.; Fletcher, P.C.; Farooqi, I.S. Divergent Effects of Central Melanocortin Signalling on Fat and Sucrose Preference in Humans. Nat. Commun. 2016, 7, 13055.
  94. Panaro, B.L.; Cone, R.D. Melanocortin-4 Receptor Mutations Paradoxically Reduce Preference for Palatable Foods. Proc. Natl. Acad. Sci. USA 2013, 110, 7050–7055.
  95. Lippert, R.N.; Ellacott, K.L.J.; Cone, R.D. Gender-Specific Roles for the Melanocortin-3 Receptor in the Regulation of the Mesolimbic Dopamine System in Mice. Endocrinology 2014, 155, 1718–1727.
  96. Eliason, N.L.; Martin, L.; Low, M.J.; Sharpe, A.L. Melanocortin Receptor Agonist Melanotan-II Microinjected in the Nucleus Accumbens Decreases Appetitive and Consumptive Responding for Food. Neuropeptides 2022, 96, 102289.
  97. Lim, B.K.; Huang, K.W.; Grueter, B.A.; Rothwell, P.E.; Malenka, R.C. Anhedonia Requires MC4R-Mediated Synaptic Adaptations in Nucleus Accumbens. Nature 2012, 487, 183–189.
  98. Shanmugarajah, L.; Dunigan, A.I.; Frantz, K.J.; Roseberry, A.G. Altered Sucrose Self-Administration Following Injection of Melanocortin Receptor Agonists and Antagonists into the Ventral Tegmental Area. Psychopharmacology 2017, 234, 1683–1692.
  99. Yen, H.-H.; Roseberry, A.G. Decreased Consumption of Rewarding Sucrose Solutions after Injection of Melanocortins into the Ventral Tegmental Area of Rats. Psychopharmacology 2015, 232, 285–294.
  100. Pandit, R.; Omrani, A.; Luijendijk, M.C.M.; de Vrind, V.A.J.; Van Rozen, A.J.; Ophuis, R.J.A.O.; Garner, K.; Kallo, I.; Ghanem, A.; Liposits, Z.; et al. Melanocortin 3 Receptor Signaling in Midbrain Dopamine Neurons Increases the Motivation for Food Reward. Neuropsychopharmacology 2016, 41, 2241–2251.
  101. Allen, A.T.; Heaton, E.C.; Shapiro, L.P.; Butkovich, L.M.; Yount, S.T.; Davies, R.A.; Li, D.C.; Swanson, A.M.; Gourley, S.L. Inter-Individual Variability Amplified through Breeding Reveals Control of Reward-Related Action Strategies by Melanocortin-4 Receptor in the Dorsomedial Striatum. Commun. Biol. 2022, 5, 116.
  102. Pandit, R.; van der Zwaal, E.M.; Luijendijk, M.C.M.; Brans, M.A.D.; van Rozen, A.J.; Oude Ophuis, R.J.A.; Vanderschuren, L.J.M.J.; Adan, R.A.H.; la Fleur, S.E. Central Melanocortins Regulate the Motivation for Sucrose Reward. PLoS ONE 2015, 10, e0121768.
  103. Figlewicz, D.P.; Jay, J.L.; Acheson, M.A.; Magrisso, I.J.; West, C.H.; Zavosh, A.; Benoit, S.C.; Davis, J.F. Moderate High Fat Diet Increases Sucrose Self-Administration in Young Rats. Appetite 2013, 61, 19–29.
  104. Cabeza de Vaca, S.; Hao, J.; Afroz, T.; Krahne, L.L.; Carr, K.D. Feeding, Body Weight, and Sensitivity to Non-Ingestive Reward Stimuli during and after 12-Day Continuous Central Infusions of Melanocortin Receptor Ligands. Peptides 2005, 26, 2314–2321.
  105. Grieb, Z.A.; Cross, E.A.; Albers, H.E. Alpha-Melanocyte-Stimulating Hormone (AMSH) Modulates the Rewarding Properties of Social Interactions in an Oxytocin Receptor-Dependent Manner in Syrian Hamsters (Mesocricetus Auratus). Physiol. Behav. 2022, 252, 113828.
  106. Klawonn, A.M.; Fritz, M.; Nilsson, A.; Bonaventura, J.; Shionoya, K.; Mirrasekhian, E.; Karlsson, U.; Jaarola, M.; Granseth, B.; Blomqvist, A.; et al. Motivational Valence Is Determined by Striatal Melanocortin 4 Receptors. J. Clin. Investig. 2018, 128, 3160–3170.
  107. Qu, N.; He, Y.; Wang, C.; Xu, P.; Yang, Y.; Cai, X.; Liu, H.; Yu, K.; Pei, Z.; Hyseni, I.; et al. A POMC-Originated Circuit Regulates Stress-Induced Hypophagia, Depression, and Anhedonia. Mol. Psychiatry 2020, 25, 1006–1021.
  108. Legrand, R.; Lucas, N.; Breton, J.; Déchelotte, P.; Fetissov, S.O. Dopamine Release in the Lateral Hypothalamus Is Stimulated by α-MSH in Both the Anticipatory and Consummatory Phases of Feeding. Psychoneuroendocrinology 2015, 56, 79–87.
  109. Rudman, D.; Hollins, B.M.; Kutner, M.H.; Moffitt, S.D.; Lynn, M.J. Three Types of Alpha-Melanocyte-Stimulating Hormone: Bioactivities and Half-Lives. Am. J. Physiol. Metab. 1983, 245, E47–E54.
  110. Di, L. Strategic Approaches to Optimizing Peptide ADME Properties. AAPS J. 2015, 17, 134–143.
  111. Lamers, C. Overcoming the Shortcomings of Peptide-Based Therapeutics. Futur. Drug Discov. 2022, 4.
  112. Wilson, J. Low Permeability of the Blood-Brain Barrier to Nanomolar Concentrations of Immunoreactive Alpha-Melanotropin. Psychopharmacology 1988, 96, 262–266.
  113. Kiss, J.Z.; Mezey, E.; Cassell, M.D.; Williams, T.H.; Mueller, G.P.; O’Donohue, T.L.; Palkovits, M. Topographical Distribution of Pro-Opiomelanocortin-Derived Peptides (ACTH/β-END/α-MSH) in the Rat Median Eminence. Brain Res. 1985, 329, 169–176.
  114. Van Houten, M.; Khan, M.N.; Walsh, R.J.; Baquiran, G.B.; Renaud, L.P.; Bourque, C.; Sgro, S.; Gauthier, S.; Chretien, M.; Posner, B.I. NH2-Terminal Specificity and Axonal Localization of Adrenocorticotropin Binding Sites in Rat Median Eminence. Proc. Natl. Acad. Sci. USA 1985, 82, 1271–1275.
  115. Tatro, J.B. Melanotropin Receptors in the Brain Are Differentially Distributed and Recognize Both Corticotropin and α-Melanocyte Stimulating Hormone. Brain Res. 1990, 536, 124–132.
  116. Tatro, J.B. Brain Receptors for Central and Peripheral Melanotropins. Ann. N. Y. Acad. Sci. 1993, 680, 621–625.
  117. Potaman, V.N.; Antonova, L.V.; Dubynin, V.A.; Zaitzev, D.A.; Kamensky, A.A.; Myasoedov, N.F.; Nezavibatko, V.N. Entry of the Synthetic ACTH(4–10) Analogue into the Rat Brain Following Intravenous Injection. Neurosci. Lett. 1991, 127, 133–136.
  118. Shevchenko, K.V.; Nagaev, I.Y.; Alfeeva, L.Y.; Andreeva, L.A.; Kamenskii, A.A.; Levitskaya, N.G.; Shevchenko, V.P.; Grivennikova, I.A.; Myasoedov, N.F. Kinetics of Semax Penetration into the Brain and Blood of Rats after Its Intranasal Administration. Russ. J. Bioorganic Chem. 2006, 32, 57–62.
  119. Trivedi, P.; Jiang, M.; Tamvakopoulos, C.C.; Shen, X.; Yu, H.; Mock, S.; Fenyk-Melody, J.; Van der Ploeg, L.H.; Guan, X.-M. Exploring the Site of Anorectic Action of Peripherally Administered Synthetic Melanocortin Peptide MT-II in Rats. Brain Res. 2003, 977, 221–230.
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