The Melanocortin System: A Promising Target for the Development of New Antidepressant Drugs

Abstract

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. The purpose of this review was to discuss the possibility of affecting these disturbances by targeting the melanocortin system, which includes adrenocorticotropic hormone-activated receptors and their peptide ligands (melanocortins). The melanocortin system is involved in the regulation of various processes in the brain and periphery. Melanocortins, including peripherally administered non-corticotropic agonists, regulate HPAA activity, exhibit anti-inflammatory effects, stimulate the levels of neurotrophic factors, and enhance hippocampal neurogenesis and neurotransmission. Therefore, endogenous melanocortins and their analogs are able to complexly affect the functioning of those body’s systems that are closely related to depression and the effects of antidepressants, thereby demonstrating a promising antidepressant potential.

Involvement of the Melanocortin System in the Regulation of Circadian and Behavioural Mechanisms in Zebrafish

“…Studies carried out in mammals suggest an MC4R role in the regulation of the HPA axis (Markov et al, 2023;Micioni Di Bonaventura et al, 2022). Under stress conditions, the expression of POMC, α-MSH and MC4Rs rises in the hypothalamus and amygdala, both known by their role in the regulation of emotional behaviours.…”

“…In mice and rats, ICV administration of α-MSH or MTII induces CRH release, correlated with increased ACTH and corticosterone synthesis, the main glococcorticoid in rodents, and promotes anxiety-like behaviours such as grooming. All these effects are reversed by MC4R antagonists such as HS014 or SHU9119 (Markov et al, 2023;Micioni Di Bonaventura et al, 2022). However, loss of MC4R function can have no effects on basal ACTH levels in rats besides HPA axis low activation under an acute stressor (Ryan et al, 2014).…”

“…The melanocortin system has been indirectly linked with mood disorders such as anxiety and depression since an unbalanced energy intake leading to either enhanced emotional eating or loss of appetite are shared symptoms (Markov et al, 2023). Common hallmarks of depression and anxiety are hyperactivation of the HPA axis (Ceruso et al, 2020), together with the alteration in central monoamine neurotransmission like low levels of serotonin, dopamine and norepinephrine .…”

“…The association between obesity and depression has led to the exploration of new therapeutic alternatives targeting the melanocortin system (Scott et al, 2008;Schachter et al, 2018;Markov et al, 2023). In mice, melanocortin peptides have been proven to increase dopaminergic neurotransmission (Roseberry et al, 2015).…”