Facilitation of Benzodiazepine Discontinuation by Melatonin

Garfinkel, Doron; Zisapel, Nava; Wainstein, Julio; Laudon, Moshe

doi:10.1001/archinte.159.20.2456

Cited by 114 publications

(72 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[111][112][113] In humans, MLT has been used to reduce or eliminate benzodiazepine administration in elderly patients. 114 Still the receptor mediating the anxiety-like effect of MLT was unknown. The recent development of selective MT 2 receptor agonists and the use of selective antagonists have shed light on the distinct role of each MLT receptor subtype in the regulation of anxiety.…”

Section: Melatonin and Anxietymentioning

confidence: 99%

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

155

126

View full text Add to dashboard Cite

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...

show abstract

Section: Melatonin and Anxietymentioning

confidence: 99%

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

155

126

View full text Add to dashboard Cite

show abstract

“…Importantly, melatonin potentiates the effects of GABA-A receptor modulators (i.e. benzodiazepine and non-benzodiazepine hypnotics) [46,65], and co-administration of melatonin during the withdrawal period is thus useful to facilitate discontinuation of hypnotic drugs [66].…”

Section: Homeostatic and Circadian Sleep Regulationmentioning

confidence: 99%

Sleep and sleep disturbances: biological basis and clinical implications

Zisapel

2007

Cell. Mol. Life Sci.

171

120

View full text Add to dashboard Cite

Sleep is a neurochemical process involving sleep promoting and arousal centers in the brain. Sleep performs an essential restorative function and facilitates memory consolidation in humans. The remarkably standardized bouts of consolidated sleep at night and daytime wakefulness reflect an interaction between the homeostatic sleep need that is manifested by increase in sleep propensity after sleep deprivation and decrease during sleep and the circadian pacemaker. Melatonin, the hormone produced nocturnally by the pineal gland, serves as a time cue and sleep-anticipating signal. A close interaction exists between the sleep-wake, melatonin, core temperature, blood pressure, immune and hormonal rhythms leading to optimization of the internal temporal order. With age the robustness of the circadian system decreases and the prevalence of sleep disorders, particularly insomnia, increases. Deviant sleep patterns are associated with increased risks of morbidity, poor quality of life and mortality. Current sleep pharmacotherapies treat insufficient sleep quantity, but fail to improve daytime functioning. New treatment modalities for sleep disorders that will also improve daytime functioning remain a scientific and medical challenge.

show abstract

“…However, previous studies indicated that melatonin may potentiate the hypnotic effects of GABA(A) receptor modulators (i.e., benzodiazepine and non-benzodiazepine hypnotics) (Ferini-Strambi et al, 1995;Garfinkel et al, 1997;Wesensten et al, 2005). Furthermore, co-administration of melatonin during the withdrawal period is thus useful to facilitate discontinuation of hypnotic drugs (Garfinkel et al, 1999). Thus, it appears important to be aware about the safety profiles of the combination of zolpidem and PR-M in elderly subjects.…”

Section: Introductionmentioning

confidence: 99%