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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]. 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]. Transcriptome-wide association studies indicate changes in the expression of a large number of genes in depression [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].
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]. 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]. 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]. 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]. 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]. 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] 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].
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]. 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]. 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].
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], other authors do not detect any differences in the plasma level of α-MSH between MDD patients and healthy controls [301]. There were no differences between depressed patients and healthy controls in α-MSH and ACTH levels in cerebrospinal fluid and plasma [302]. 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].
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], rs111734014 polymorphism in the MC2R gene, and rs2236700 in the MC5R gene are associated with the risk of MDD [305].
Indirectly, the possible involvement of the melanocortin system in depression is indicated by studies demonstrating a close relationship between depression and obesity [306,307]. 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].
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], MCL0129 [313], MCL0042 [314], and the MC3R/MC4R antagonist SHU 9119 [315,316]. Intranasal infusion of HS014 also prevents development of depressive-like and anxiety-like behavior [317,318]. 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]. Centrally administered MCRs agonists exert anxiogenic effects. The level of anxiety increases after central administration of α-MSH [320,321] and ACTH1-24 [322], but not of ACTH4-10 and ACTH11-24. Similar effects have been observed after α-MSH administration into the medial preoptic area [323]. MC4R signaling in the dorsal raphe nucleus affects anxiety and depression-like behavior [324]. 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].
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], while others do not demonstrate any influence of α-MSH on the depression-like behavior [327]. 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]. IP administered ACTH6-9-Pro-Gly-Pro also exerts antidepressant and anxiolytic effects [329].
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].
Antidepressants can also affect the melanocortin system. Fluoxetine administration increases POMC expression and reduces MC4R expression in the hypothalamus [334]. POMC mRNA levels in the arcuate nucleus of the hypothalamus are increased following chronic treatment with phenelzine and idazoxan [335]. However, orally administered fluoxetine decrease α-MSH levels in the PVN of the hypothalamus [336].
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]. Deletion of both alleles of the MC4R decreases preference for palatable high-sucrose foods in wild-type mice [338]. Global deletion of the MC3R decreases sucrose intake and preference in female but not male mice [339].
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]. Chronic stress-elicited anhedonia requires activation of MC4R in the NAc [293]. Injection of MT-II into the VTA decreases motivation to obtain sucrose pellets on both fixed ratio and progressive ratio schedules of reinforcement [341] and decreases the intake of sucrose solution [342]. 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]. MC4R in the dorsomedial striatum appears to propel reward-seeking behavior [344].
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]. Central AGRP administration results in significantly increased motivation for sucrose solution in rats under a progressive ratio schedule of reinforcement [346]. 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]. However, ICV infusion of α-MSH decreases the rewarding properties of social interactions (rewarding stimulus) in Syrian hamsters [348].
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].
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]. 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].
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]. 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].
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]. How melanocortins exert central effects after peripheral administration remains unknown. Circumventricular organs may play an important role in this process. Melanocortins [356] and their binding sites [357,358,359] 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] and after intranasal administration [361]. 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]. It is possible that small-molecules agonists and antagonists of melanocortin receptors will be able to cross the blood-brain barrier much more easily.
This entry is adapted from the peer-reviewed paper 10.3390/ijms24076664
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