Serotonergic system

The synthesis of melatonin occurs within pinealocytes through the conversion of the neurotransmitter serotonin. The enzyme AANAT is responsible for the conversion of serotonin into N-acetyls serotonin, which serves as the precursor for melatonin. Additionally, this enzyme plays a regulatory role in the circadian clock [36]. It has been shown that N-acetyl transferase activity increases 150 times with noradrenergic stimulation. Consequently, this heightened enzymatic activity leads to an augmented synthesis of melatonin specifically during the nocturnal period [37]. It is known that the pineal gland exhibits a consistent release of serotonin. This constant release also shows a diurnal pattern, characterized by elevated levels during daylight hours and reduced levels during nighttime [38, 39]. N-Acetyl serotonin is also released from the pineal gland and has been shown to stimulate tropomyosin receptor kinase B (TrkB) receptor-mediated release of brain-derived neurotrophic factor (BDNF) [40]. The primary inference that can be drawn from all this information is that the noradrenergic, serotonergic, and melatonergic systems are closely intertwined and intricately related to each other.

Serotonergic neurons exhibit a strong association with the SCN. SCN receives direct input from serotonergic neurotransmission that originates from the median raphe nucleus. Additionally, it receives indirect input through the neuropeptide Y (NPY) pathway from the intergeniculate leaflet, which is regulated by the dorsal raphe nucleus. Subsequently, the SCN transmits polysynaptic efferent signals to the midbrain serotonergic nuclei, predominantly via the dorsomedial hypothalamus and its associated projections [41]. Both serotonin and NPY are involved in the regulation of the circadian system’s response to light, as well as in the modulation of the central clock’s period and phase through feedback mechanisms related to behavioral arousal and locomotor activity [42, 43]. It is believed that the serotonergic and circadian systems have a clinical correlation. In non-seasonal depression, it has been observed that circadian light therapy enhances and accelerates the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs) [44]. In addition to the effect of light exposure on mood, melatonergic receptor agonists such as agomelatine which is being used to treat depression, further demonstrates the interdependence of both systems [45]. On the other hand, according to studies, melatonin itself does not demonstrate antidepressant properties. However, it has the potential to enhance the effects of other antidepressant medications [46, 47]. In contrast, previous studies have demonstrated that the acute administration of citalopram (SSRI) has the effect of heightening the responsiveness of the circadian rhythm to light stimuli and intensifying the inhibition of melatonin production [48]. Hence, it can be suggested that a reciprocal pharmacological interaction exists between the serotonergic and melatonergic systems. The observation that antidepressants exert a suppressive influence on melatonin, whereas melatonergic agents and melatonin are employed in the management of depression, underscores a paradox that calls for additional clarification [49]. In addition, this point also introduces the potential for chronobiological approaches, which propose that the timing of melatonergic agent administration could impact the effectiveness of depression treatment. A considerable body of research in the fields of pharmacokinetics and pharmacodynamics has demonstrated that the efficacy of numerous antidepressant medications can be influenced by the timing of their administration [50]. Serotonin may also be produced by mitochondria in all cells. This hypothesis places melatonin production at the center of all cellular metabolism. From this point of view, the use of SSRIs may also increase the amount of cellular serotonin that is readily available and accelerate the release of melatonin from all cells, central and peripheral [51]. Although it is difficult to draw definitive and universally applicable conclusions, the interconnectedness of the melatonergic and serotonergic systems can potentially aid in resolving this matter. Additional investigation into the complex interplay among these systems has the potential to yield valuable insights.

Noradrenergic system

Norepinephrine and epinephrine demonstrate a circadian rhythm of secretion within the human body. Plasma concentrations in humans exhibit a decrease during nighttime and an increase during daytime. Furthermore, it has been observed that during the sleep period, there is an additional reduction of approximately 30% in their plasma levels [52]. In contrast, the release of norepinephrine by central sympathetic nerve terminals is 100 times higher at night [30]. This observation suggests that there are variations in noradrenergic rhythms across different physiological regions. Norepinephrine, through the activation of beta-2 receptors, stimulates the synthesis of melatonin from serotonin in the pineal gland, which is characterized by a rich noradrenergic innervation. The prevailing hypothesis proposes that the mechanism underlying this induction is primarily mediated via the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling pathway [53, 54]. Based on this hypothesis, it is postulated that heightened levels of cAMP, as a consequence of sympathetic noradrenergic stimulation, trigger the phosphorylation of AANAT. This enzyme plays a pivotal role in the synthesis of melatonin. The activation of PKA is responsible for this process. During the period of daylight, when the stimulation of noradrenaline ceases, the degradation of this enzyme occurs rapidly [55]. Therefore, norepinephrine carries a crucial function as a prominent stimulus in triggering the secretion of melatonin during nocturnal periods.

Yet it is also necessary to mention that norepinephrine serves as a central neurotransmitter that plays a role in the regulation of wakefulness. While it is involved in the stimulation of melatonin production, it also plays a crucial role in maintaining wakefulness [56]. The previously mentioned plasma circadian rhythm of norepinephrine serves as an indication of its involvement in the regulation of wakefulness. This role of norepinephrine is closely linked to the presence of light. The light signals originating from the retina that are transmitted to the SCN also project to the dorsal medial hypothalamus (DMH). The dorsomedial hypothalamus transmits these signals to the regions responsible for promoting wakefulness and enhancing arousal, thereby acting as an activating stimulus. The locus coeruleus is a notable region responsible for promoting wakefulness, as it plays a central role in the release of norepinephrine within the brain [56, 57]. Melatonin, on the other hand, acts on the SCN via MT1 receptors, inhibiting the firing of these neurons and promoting sleep induction [56].

Based on the available evidence, it can be suggested that there exists a bidirectional relationship between norepinephrine and melatonin [56]. Norepinephrine plays a role in facilitating the state of wakefulness, both at the physiological level within the body and through central nervous mechanisms that involve the locus coeruleus. Furthermore, it has been observed that it enhances the secretion of melatonin during nighttime via metabolic pathways. The melatonin that is released subsequently inhibits norepinephrine signaling, resulting in a decrease in wakefulness. The complete understanding of the intricate equation presented remains unclear and the investigation into the mechanism by which norepinephrine promotes wakefulness in specific contexts while inducing sleep in others necessitates additional studies.

Dopaminergic system

Dopamine, as a neuromodulator, plays a significant role in regulating both central and peripheral circadian rhythms. Its functions involve locomotor activity, reward mechanisms, and learning processes. Multiple studies have been conducted on both the SCN and peripheral brain regions, yielding a substantial body of evidence indicating that dopamine exerts an impact on neural clock genes and proteins [58].

Dopamine is found in the retina as a neuromodulator and plays an important role in facilitating adaptation to light [59]. Research has demonstrated that dopamine displays diurnal rhythms not only in the retina, but also in the olfactory bulb [60]. It has been shown that the rhythmic functioning of dopamine in the retina is dependent on the presence of melatonin. When melatonin is not present, the regularity of this rhythmic pattern comes to an end [61]. Research has also demonstrated that dopamine, by interacting with D2 receptors, exerts an inhibitory effect on the activity of AANAT. Thus, it is suggested that a reciprocal inhibition exists between melatonin and dopamine within the retina [58]. However, it has been reported that the rhythmic activity of dopamine is not limited to the retina but also occurs in other regions such as the striatum, midbrain, and hypothalamus, exhibiting diurnal activity [58].

It has been demonstrated that melatonin inhibits the hypothalamic release of dopamine. This inhibition is closely associated with the secretion of prolactin and is most pronounced in the tuberoinfundibular pathway [62, 63]. In addition, it has been shown that melatonin inhibits the release of dopamine via the nigrostriatal pathway [64, 65]. Additionally, the inhibitory effect of melatonin on striatal neurons may be associated with the suppression of glutamatergic signaling through N-methyl-D-aspartatic (NMDA) receptors [62]. This circumstance has significant clinical implications. Melatonin, which is being evaluated for its neuroprotective properties in Parkinson’s disease, may exacerbate the condition by inhibiting dopamine release. Animal studies support this hypothesis, and it has even been suggested that melatonin antagonism could be beneficial in the treatment of Parkinson’s disease [62, 66]. Therefore, it is advised to exercise caution when using melatonin in neurodegenerative diseases.

Impairments in melatonin release have been observed both in the pathogenesis of schizophrenia and secondary to antipsychotic drug use. Both decreased melatonin release and phase shift have been reported in schizophrenia patients [67, 68]. Accordingly, the use of melatonin as a supplement may replace the impaired pineal gland function seen in schizophrenia and may also prevent possible adverse effects of antipsychotics [69]. Thus melatonin’s suppressive effects on the dopaminergic system may have therapeutic potential in tardive dyskinesia, which is an adverse effect of antipsychotic use, characterized by involuntary facial and body movements. It is believed that dopamine receptor hypersensitivity contributes to this adverse effect. In treating tardive dyskinesia, the modulatory effect of melatonin on the dopaminergic system may therefore be beneficial. There are positive reports despite some contradictory findings from clinical studies in this area [70–72].

Cholinergic system

Cholinergic systems exhibit a distinct circadian rhythm in mammals. The amount of acetylcholine (ACh) in the brain increases during wakefulness and physical activity. In general, the circadian rhythm in the cholinergic system is characterized by an increase in ACh release during the active phase (dark phase for nocturnal species and light phase for diurnal species), as well as an increase in choline acetyltransferase activity and a decrease in acetylcholinesterase activity. In addition to exhibiting diurnal rhythmicity, the cholinergic system is regarded as an arousal-inducing mechanism [73, 74].

Cholinergic signaling originating from the laterodorsal tegmental (LDT) and pedunculopontine tegmental nuclei (PPT) and the basal forebrain, projecting to the pontine reticular formation, plays a central role in promoting wakefulness. Although cholinergic system activity decreases during non-rapid eye movement (REM) sleep, cholinergic signaling originating from these regions also supports the generation of REM sleep [73, 75]. This phenomenon is explained by two distinct cholinergic transmission pathways originating from the LDT/PPT. One pathway is active during both wakefulness and REM sleep, while the other pathway is only active during wakefulness [76].

It is believed that melatonin, with its protective effect on cholinergic neurons, may be beneficial, especially for dementia patients [77–79]. Extensive research has been conducted on the possible protective effects of exogenous melatonin in dementia patients, but the current understanding of the cross-talk between endogenous melatonin and cholinergic neurons is limited. Endogenous nocturnal melatonin release improves the function of nicotinic ACh receptors, according to one study [78]. The authors of this study have linked this finding to the theory that the age-related decline in melatonin release may contribute to the degeneration of cholinergic neurons [78]. On the other hand, melatonergic stimulation has been shown to increase the synaptic activity and expression of nicotinic ACh receptors. This finding provides an important clue as to the mechanisms through which melatonin protects and strengthens cholinergic neurons [78]. In addition, an experimental study suggested that melatonin may contribute to the protection of the duodenal barrier by enhancing nicotinic ACh receptor-mediated cholinergic stimulation from the vagal nerve. This finding may also be associated with the potentiating effect of melatonin on cholinergic stimulation [80]. Also, it must be noted that tacrine-melatonin hybrid therapy which is being developed against dementia, increases cholinergic transmission both by inhibiting acetylcholinesterase and strengthening cholinergic neurotransmission [81].

The observation that cholinergic agents activate specific neurons in the SCN provides insight into the relationship between the central centers that regulate circadian rhythm and cholinergic mechanisms [82]. It has been also observed that the administration of the ACh receptor agonist carbachol produces effects similar to the influence of light in the SCN [83]. This relationship, however, is believed to be indirectly related to the light-SCN relationship and originates from a modulatory function of ACh [84].

When all this information is considered, it becomes clear that ACh has a close connection with circadian rhythm and sleep. However, no direct cross-talk or projection between melatonin and the cholinergic system has been identified. Given the substantial protective and strengthening effect of melatonin on cholinergic neurons and the influence of cholinergic neurons on circadian rhythms and sleep, it is remarkable that there is no direct interaction between these two systems has been found yet. Additional research is required to investigate this uncharted area of the literature.

Histaminergic system

The tuberomamillary nucleus (TMN) of the posterior hypothalamus is the primary location of histaminergic neurons. This nucleus projects to numerous regions of the CNS, including the arousal-inducing regions of the basal forebrain and the orexin-containing lateral hypothalamus [85].

Histamine produces its effects via four G protein-coupled receptors, three of which are expressed in the CNS (H1, H2, and H3). Particularly, H1 and H3 receptors play a significant role in sleep promotion in the CNS. The majority of antihistamines induce sedation by blocking H1 receptors, whereas the H3 inverse agonist pitolisant was recently approved by the Food and Drug Administration (FDA) for treating insomnia [86].

The circadian rhythm modulates the expression of the histidine decarboxylase (HDC) gene, which encodes the most important enzyme in histamine synthesis. During active hours, HDC expression increases, whereas during rest hours, HDC expression can drop below detectable levels in certain cells [86]. The circadian changes in HDC gene expression have been observed to be absent in “Bmal1” gene knockout mice, which is one of the central genes governing the circadian rhythm [87]. Furthermore, it has been shown that in HDC knockout mice, although the expression of clock genes remains intact in the SCN, it is significantly disrupted in regions such as the cortex and striatum [88].

The disruption of the sleep-wake cycle observed in zebrafish lacking melatonin production (AANAT knockout) has been reversed by treatment with the H1 receptor antagonist pyrilamine in a study [89]. This finding suggests the presence of a central communication between histamine and melatonin [35].

Mast cell activation is an additional critical site where melatonin and histamine release intersect. It has been demonstrated that the MT1 and MT2 receptors found on mast cells have anti-inflammatory effects by preventing the release of histamine, and that the circadian rhythm influences this process [35, 90–92]. The investigation of the intersection points between the histaminergic and melatonergic systems presents a compelling subject for academic study, offering potential insights into the intricate connection between sleep and immunity.

Experimental production of dual-acting ligands that exert their effects via histamine and melatonin pathways is underway [93]. These agents possess the capacity to influence various pathologies by means of both neuropsychiatric and immunological mechanisms, thereby providing insights into certain physiopathological pathways that remain incompletely understood.

Ramelteon

Ramelteon is a synthetic analogue of melatonin. The compound functions as an agonist on melatonin MT1 and MT2 receptors. The oral bioavailability of it is quite limited, approximately 2%. This medication is employed for the therapeutic management of insomnia and does not exhibit the development of tolerance towards its sleep latency-reducing efficacy. No withdrawal effects have been observed. The half-life is 1–2 h [94, 95]. It has been shown in animal experiments that acute use does not impair memory, learning, and motor function [96, 97]. It has also been reported in animal experiments that it does not have rewarding and addictive effects [96]. The adverse effects observed in clinical use, such as drowsiness, dizziness, and fatigue, are generally mild to moderate and have been reported in a small number of patients [95].

In Alzheimer’s patients, a significant decrease in melatonin levels and degeneration of SCN neurons have been observed [95, 98]. Moreover, a number of clinical studies have provided evidence supporting the substantial therapeutic benefits of melatonin in the management of sleep and circadian disruptions among individuals diagnosed with Alzheimer’s disease [99]. Melatonin is also well known to have significant neuroprotective effects [100]. Due to ramelteon’s higher receptor affinity and longer half-life, it has been suggested that it may have potential benefits in the treatment of dementia. According to reports in the scientific literature, ramelteon shows neuroprotective properties comparable to melatonin in Alzheimer’s disease patients [101]. On the other hand, it is suggested that ramelteon, similar to melatonin, may increase the levels of BDNF and other neurotrophic factor levels [102].

Ramelteon’s potential areas of use are not limited to dementia alone. A study has reported its potential preventive effect on the development of delirium [103]. Moreover, interestingly, ramelteon has been shown to suppress endometrial cancer cells in vitro, and in another study, both agomelatine and ramelteon have demonstrated the ability to suppress glioblastoma cells [104, 105].

In spite of ramelteon’s limited antioxidant efficacy, the findings regarding its tumor-suppressing effects are noteworthy [106]. The intracellular pathways and mechanisms through which the selective activity on MT1/MT2 receptors may exert tumor-suppressive or neurotrophic factor-enhancing effects independent of the antioxidant effect remain unclear.

Agomelatine

Agomelatine is an MT1/MT2 receptor agonist and a 5HT2C antagonist. Its half-life is 2.3 h [107]. Its bioavailability from oral route is less than 5% [108]. It is believed that the drug’s dual action on melatonin and serotonin receptors creates a synergistic effect against mood disorders. Considering the close association between circadian rhythm disturbances and depression, this relationship is particularly important [109].

Agomelatine has been shown to exhibit circadian rhythm synchronizing effects similar to melatonin, as demonstrated in animal experiments conducted in constant darkness [110–112]. It has also remarkably been reported that agomelatine can modulate disrupted sleep-wake cycles and circadian rhythms in animals even when the circadian rhythm is disrupted by depression models and not by light exposure [113]. In addition, a clinical study showed that agomelatine increased slow-wave sleep duration in depressed patients without affecting REM sleep duration [114].

In addition to its circadian rhythm-regulating properties, agomelatine is notable for its antidepressant properties. It is important to note that, unlike agomelatine, melatonin alone has no antidepressant effects [115]. Animal studies utilizing various depression models, such as the forced swim model, learned helplessness model, chronic moderate stress model, psychosocial stress model, and genetic models, have demonstrated the effectiveness of agomelatine in treating depression in a variety of experimental settings [116]. In addition, many animal studies have demonstrated anxiolytic effects at doses where antidepressant effects are observed [116, 117]. The anxiolytic effect has also been demonstrated in clinical trials [118, 119]. The antagonism of 5HT2C plays an essential role in the development of the aforementioned antidepressant and anxiolytic effects by increasing dopamine and norepinephrine in the prefrontal cortex [120].

On one hand, it has been demonstrated that agomelatine may improve cognitive performance regardless of depressive disorder [121]. This can be associated with research findings that demonstrate the potential of agomelatine to enhance neurotrophic factors [122, 123]. On the other hand, the neurogenesis enhancing effect of agomelatine may contribute to its therapeutic effects in the treatment of depression which is a disorder characterized by neuronal and glial cell loss and reduced neuroplasticity [124, 125].

Given the abundance of research supporting cognitive function enhancing effects, it is worth noting that positive outcomes have also been observed in studies regarding Alzheimer’s disease. The findings of an animal study indicate that agomelatine exhibits the capacity to mitigate depressive behaviors induced by amyloid-beta and effect the accumulation of amyloid-beta in the hippocampus [126]. Additionally, it has been demonstrated that agomelatine can reduce amyloid-beta phosphorylation in cell culture [126]. Also in clinical studies regarding dementia, positive effects of agomelatine on psychiatric symptoms have also been observed [127]. All of these findings suggest that, similar to ramelteon, agomelatine has significant therapeutic potential for Alzheimer’s disease and dementia.

It is also believed that agomelatine could also be helpful to improve specific psychiatric conditions, such as apathy and anhedonia, in addition to depression, anxiety, and concomitant sleep disorders [120]. In addition, there have been reports that agomelatine exhibits suppressive effects on cancer cells in cell culture [128–130]. It has also been reported that agomelatine reduces endothelial and mononuclear cell adhesion induced by angiotensin-2, thereby possessing a positive potential in endothelial vascular pathologies. This suggests that agomelatine may have beneficial effects on endothelial dysfunction-related conditions [131]. These findings form pharmacological clues that indicate there are still unresolved aspects of the physiology of melatonergic receptors.

In addition to all of these advantages, it is essential to remember that agomelatine may cause elevated liver enzymes and is contraindicated in patients with elevated liver enzymes [132, 133].

Tasimelteon

Tasimelteon is a melatonin analog that received FDA approval in 2014 for the treatment of non-24-h sleep-wake disorder [134]. This medication is a full agonist for melatonin MT1 and MT2 receptors and is known to reset pacemaker cells in the SCN. It has a threefold greater affinity for MT2 receptors than MT1 receptors [134]. No interactions with other receptors have been observed [135]. Based on the findings of the tasimelteon for non-24-hour sleep-wake disorder in totally blind people (SET and RESET) clinical trial, this medication is recommended for the treatment of sleep disorders in completely blind individuals. In general, it is well-tolerated and does not carry a significant risk of adverse effects [136].