The role of dorsal raphe nucleus serotonergic and non-serotonergic neurons, and of their receptors, in regulating waking and rapid eye movement (REM) sleep

Monti, Jaime M.

doi:10.1016/j.smrv.2009.10.003

Cited by 122 publications

(88 citation statements)

References 75 publications

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“…99 Compared with wild-type controls, MT 2 -/-mice 40 displayed a significant decrease in the amount of NREMS during the 24-hour period (-17%), with the decrease mainly due to changes occurring during the light/inactive phase of the 12-hour light-dark cycle. 33 No variation in the amount of REMS was found.…”

Section: Mt 2 Knockout Mice and Sleepmentioning

confidence: 94%

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

Comai

Gobbi

2014

J Psychiatry Neurosci

153

126

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IntroductionMelatonin (MLT) is a neurohormone synthesized from serotonin (5-HT) and secreted foremost by the mammalian pineal gland following a distinct circadian rhythm with the acrophase during the dark phase and the nadir during the light phase in both diurnal and nocturnal species.1 A typical human adult's average daytime and nighttime levels of blood MLT are approximately 10 pg/mL and 60 pg/mL, respectively.2 Its production is controlled through the suprachiasmatic nucleus (SCN) by the photoperiod, peaking at night and dropping during the day. Melatonin is involved in numerous physiologic processes, including circadian rhythms, mood regulation, anxiety, sleep, appetite, immune responses and cardiac functions. 3,4 Most of the effects of MLT in the brain result from the activation of 2 high-affinity G-protein coupled receptors (GPCRs), MT 1 and MT 2 .5 Of note, GPCRs have a proven history of being excellent therapeutic targets. Recent market analyses indicate that 40%-50% of modern drugs and almost 25% of the top 200 best-selling drugs target GPCRs. 6 In addition to these high-affinity MLT receptors, another low-affinity MLT binding site, MT 3 , has recently been characterized as an MLT-sensitive form of the human enzyme quinone reductase 2. 7 The functional characterization of MT 1 and MT 2 receptors in target tissues is hampered by the paucity of selective MT 1 and MT 2 receptor ligands. Structural Background: Melatonin (MLT) is a pleiotropic neurohormone controlling many physiological processes and whose dysfunction may contribute to several different diseases, such as neurodegenerative diseases, circadian and mood disorders, insomnia, type 2 diabetes and pain. Melatonin is synthesized by the pineal gland during the night and acts through 2 G-protein coupled receptors (GPCRs), MT 1 (MEL1a) and MT 2 (MEL1b). Although a bulk of research has examined the physiopathological effects of MLT, few studies have investigated the selective role played by MT 1 and MT 2 receptors. Here we have reviewed current knowledge about the implications of MT 2 receptors in brain functions. Methods: We searched PubMed, Web of Science, Scopus, Google Scholar and articles reference lists for studies on MT 2 receptor ligands in sleep, anxiety, neuropsychiatric diseases and psychopharmacology, including genetic studies on the MTNR1B gene, which encodes the melatonin MT 2 receptor. Results: These studies demonstrate that MT 2 receptors are involved in the pathophysiology and pharmacology of sleep disorders, anxiety, depression, Alzheimer disease and pain and that selective MT 2 receptor agonists show hypnotic and anxiolytic properties. Limitations: Studies examining the role of MT 2 receptors in psychopharmacology are still limited. Conclusion: The development of novel selective MT 2 receptor ligands, together with further preclinical in vivo studies, may clarify the role of this receptor in brain function and psychopharmacology. The superfamily of GPCRs has proven to be among the most successful drug targets and, consequently, M...

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Section: Mt 2 Knockout Mice and Sleepmentioning

confidence: 94%

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

Comai

Gobbi

2014

J Psychiatry Neurosci

153

126

View full text Add to dashboard Cite

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“…Serotonin neurons in the DR are, in part, regulated by surrounding glutamate and GABAergic neurons which modulate serotoninergic innervation of the LDT and PPT to regulate REM/non-REM sleep [73]. It is possible that the reduced innervation of Ox may contribute to impaired regulation of sleep by serotonin neurons.…”

Section: Dysfunctional Sleepmentioning

confidence: 99%

Decreased orexin (hypocretin) immunoreactivity in the hypothalamus and pontine nuclei in sudden infant death syndrome

et al. 2015

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Infants at risk of sudden infant death syndrome (SIDS) have been shown to have dysfunctional sleep and poor arousal thresholds. In animal studies, both these attributes have been linked to impaired signalling of the neuropeptide orexin. This study examined the immunoreactivity of orexin (OxA and OxB) in the tuberal hypothalamus (n = 27) and the pons (n = 15) of infants (1-10 months) who died from SIDS compared to age-matched non-SIDS infants. The percentage of orexin immunoreactive neurons and the total number of neurons were quantified in the dorsomedial, perifornical and lateral hypothalamus at three levels of the tuberal hypothalamus. In the pons, the area of orexin immunoreactive fibres were quantified in the locus coeruleus (LC), dorsal raphe (DR), laterodorsal tegmental (LDT), medial parabrachial, dorsal tegmental (DTg) and pontine nuclei (Pn) using automated methods. OxA and OxB were co-expressed in all hypothalamic and pontine nuclei examined. In SIDS infants, orexin immunoreactivity was decreased by up to 21 % within each of the three levels of the hypothalamus compared to non-SIDS (p ≤ 0.050). In the pons, a 40-50 % decrease in OxA occurred in the all pontine nuclei, while a similar decrease in OxB immunoreactivity was observed in the LC, LDT, DTg and Pn (p ≤ 0.025). No correlations were found between the decreased orexin immunoreactivity and previously identified risk factors for SIDS, including prone sleeping position and cigarette smoke exposure. This finding of reduced orexin immunoreactivity in SIDS infants may be associated with sleep dysfunction and impaired arousal.

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“…Serotonin has complex effects on sleep architecture (58), but specifically, the 5-HT(1A) neuron is involved in regulation of sleep and REM, knockout mice without 5-HT(1A) have increased REM sleep (59). Kohyama identifies the inhibitory phase of REM sleep as being the key period of risk in SIDS and ALTE (apparent life-threatening event) subjects (60); in polygraphic sleep recordings of future SIDS victims Kahn found that 78% of events with apnoeas and bradycardia occurred during REM sleep (9).…”

Section: Hypothesized Mechanism For Sids Protection By Supine Sleepmentioning

confidence: 99%

Proposal for mechanisms of protection of supine sleep against sudden infant death syndrome: an integrated mechanism review

Bergman

2014

Pediatr Res

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Supine sleep decreases sudden infant death syndrome (SIDS) incidence, however the mechanisms for this are unclear. The triple risk model for SIDS requires that one or more underlying abnormalities of breathing or autonomic control are present; these are rare, but brainstem defects are found in most SIDS cases. Supine sleep increases sympathetic nervous system tone, and level of state organization, and may therefore act as a stressor. This is evidenced by physiological arousal, and by delayed neurodevelopment in supine compared to prone sleepers. It is argued here that prone sleep position is the biological normative standard in healthy infants, supporting autonomic regulation. During rapid eye movement (REM) sleep (and other circumstances), a parasympathetic-mediated adverse autonomic event (AAE) may be spontaneously triggered. In healthy infants, gasping initiates autoresuscitation and recovery. Hypothesis: the underlying vulnerability to SIDS is specific to autoresuscitation from an AAE, the initial serotonin-dependent gasp is commonly compromised. Serotonin metabolism defects also influence sleep architecture, increasing the likelihood of AAE. The mechanism whereby supine sleep decreases SIDS may therefore be a stressor effect, disturbing sleep architecture to decrease REM and AAEs, and increasing sympathetic tone, which may prevent and counteract the purely parasympathetic-mediated AAE, thereby decreasing the risk of SIDS.

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The role of dorsal raphe nucleus serotonergic and non-serotonergic neurons, and of their receptors, in regulating waking and rapid eye movement (REM) sleep

Cited by 122 publications

References 75 publications

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

Decreased orexin (hypocretin) immunoreactivity in the hypothalamus and pontine nuclei in sudden infant death syndrome

Proposal for mechanisms of protection of supine sleep against sudden infant death syndrome: an integrated mechanism review

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