102,342 research outputs found
Differential function of melatonin MT1 and MT2 receptors in REM and NREM sleep
No full textThe pathophysiological function of the G-protein coupled melatonin MT1 and MT2 receptors has not yet been well-clarified. Recent advancements using selective MT1/ MT2 receptor ligands and MT1/MT2 receptor knockout mice have suggested that the activation of the MT1 receptors are mainly implicated in the regulation of rapid eye movement (REM) sleep, whereas the MT2 receptors selectively increase non-REM (NREM) sleep. Studies in mutant mice show that MT1 knockout mice have an increase in NREM sleep and a decrease in REM sleep, while MT2 knockout mice a decrease in NREM sleep. The localization of MT1 receptors is also distinct from MT2 receptors; for example, MT2 receptors are located in the reticular thalamus (NREM area), while the MT1 receptors in the Locus Coeruleus and lateral hypothalamus (REM areas). Altogether, these findings suggest that these two receptors not only have a very specialized function in sleep, but that they may also modulate opposing effects. These data also suggest that mixed MT1-MT2 receptors ligands are not clinically recommended given their opposite roles in physiological functions, confirmed by the modest effects of melatonin or MT1/MT2 non-selective agonists when used in both preclinical and clinical studies as hypnotic drugs. In sum, MT1 and MT2 receptors have specific roles in the modulation of sleep, and consequently, selective ligands with agonist, antagonist, or partial agonist properties could have therapeutic potential for sleep; while the MT2 agonists or partial agonists might be indicated for NREM-related sleep and/or anxiety disorders, the MT1 agonists or partial agonists might be so for REM-related sleep disorders. Furthermore, MT1 but not MT2 receptors seem involved in the regulation of the circadian rhythm. Future research will help further develop MT1 and/or MT2 receptors as targets for neuropsychopharmacology drug development
Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: A novel target in psychopharmacology
No full textBackground: 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), MT1 (MEL1a) and MT2 (MEL1b). Although a bulk of research has examined the physiopathological effects of MLT, few studies have investigated the selective role played by MT1 and MT2 receptors. Here we have reviewed current knowledge about the implications of MT2 receptors in brain functions. Methods: We searched PubMed, Web of Science, Scopus, Google Scholar and articles reference lists for studies on MT2 receptor ligands in sleep, anxiety, neuropsychiatric diseases and psychopharmacology, including genetic studies on the MTNR1B gene, which encodes the melatonin MT2 receptor. Results: These studies demonstrate that MT2 receptors are involved in the pathophysiology and pharmacology of sleep disorders, anxiety, depression, Alzheimer disease and pain and that selective MT2 receptor agonists show hypnotic and anxiolytic properties. Limitations: Studies examining the role of MT2 receptors in psychopharmacology are still limited. Conclusion: The development of novel selective MT2 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, MT2 receptors have great potential for pioneer drug discovery in the treatment of mental diseases for which limited therapeutic targets are currently available. © 2014 Canadian Medical Association
Sleep well. Untangling the role of melatonin MT1 and MT2 receptors in sleep
No full textThe pharmacological potential of targeting selectively melatonin MT1 or MT2 receptors has not yet been exploited in medicine. Research using selective MT1/MT2 receptor ligands and MT1/MT2 receptor knockout mice has indicated that the activation of MT2 receptors selectively increases non-rapid eye movement (NREM) sleep whereas MT1 receptors seem mostly implicated in the regulation of REM sleep. Moreover, MT1 knockout mice show an increase in NREM sleep, while MT2 knockout a decrease, suggesting an opposite role of these two receptors. A recent paper in mice by Sharma et al (J Pineal Res, 2018, e12498) found that MT1 but not MT2 receptors are expressed on orexin neurons in the perifornical lateral hypothalamus (PFH). Moreover, after injecting melatonin or luzindole into the mouse PFH, the authors suggest that melatonin promotes NREM sleep because activates PFH MT1 receptors, which in turn inhibit orexin neurons that are important in promoting arousal and maintaining wakefulness. In this commentary, we have critically commented on some of these findings on the bases of previous literature. In addition, we highlighted the fact that no conclusions could be drawn on the melatonin receptor subtype mediating the effects of melatonin on sleep because the authors used the non-selective MT1/MT2 receptors antagonist luzindole. More solid research should further characterize the pharmacological function of these two melatonin receptors in sleep
Translational research in suicide: Is it possible to study suicide in animal models?
No full textSuicide constitutes a serious medical and social problem. There are several risk factors for suicide including history of mental disorders, alcohol and substance abuse, impulsive or aggressive tendencies, family history of suicide, family history of child maltreatment, previous suicide attempts, feelings of hopelessness, cultural and religious beliefs, and physical illness, in particular chronic pain. Up to date, there are no animal models of suicide mainly because there is no instance of suicide among animals. Indeed suicide occurs almost exclusively in humans giving the link to two important aspects of the human being: (1) the self- consciousness and (2) the psychological suffering. However, in experimental animals we can model several of the main risk factors for suicidal behavior. In this chapter we will thus describe the main animal paradigms of mood disorders, aggression, impulsivity, and drug abuse/dependence. Moreover, we examine the in-vivo electrophysiology technique which allows the study of the neural activity of the different neurotransmitters implicated in suicide. The combination of behavioral pharmacology and electrophysiology is currently a gold standard for the investigation of the neurobiology of mental illness and has allowed answering clinically relevant questions and developing novel and efficacious treatments in psychiatry. This approach may thus have great potential also in the field of suicide allowing to increasing our understanding of the neurobiological basis of suicide. However, to develop novel pharmacological strategies to prevent suicide attempts, more translational research in humans is needed to understand the link between depression, impulsivity, self-consciousness, and psychological suffering
Sleep-wake characterization of double MT1/MT2 receptor knockout mice and comparison with MT1 and MT2 receptor knockout mice
No full textThe neurohormone melatonin activates two G-protein coupled receptors, MT1 and MT2. Melatonin is implicated in circadian rhythms and sleep regulation, but the role of its receptors remains to be defined. We have therefore characterized the spontaneous vigilance states in wild-type (WT) mice and in three different types of transgenic mice: mice with genetic inactivation of MT1 (MT1-/-), MT2 (MT2-/-) and both MT1/MT2 (MT1-/-/MT2-/-) receptors.Electroencephalographic (EEG) and electromyographic sleep-wake patterns were recorded across the 24-h light-dark cycle. MT1-/-mice displayed a decrease (-37.3%) of the 24-h rapid eye movement sleep (REMS) time whereas MT2-/-mice showed a decrease (-17.3%) of the 24-h non rapid eye movement sleep (NREMS) time and an increase in wakefulness time (14.8%). These differences were the result of changes occurring in particular during the light/inactive phase. Surprisingly, MT1-/-/MT2-/- mice showed only an increase (8.9%) of the time spent awake during the 24-h. These changes were correlated to a decrease of the REMS EEG theta power in MT1-/-mice, of the NREMS EEG delta power in MT2-/-mice, and an increase of the REMS and wakefulness EEG theta power in MT1-/-/MT2-/- mice. Our results show that the genetic inactivation of both MT1 and MT2 receptors produces an increase of wakefulness, likely as a result of reduced NREMS due to the lack of MT2 receptors, and reduced REMS induced by the lack of MT1 receptors. Therefore, each melatonin receptor subtype differently regulates the vigilance states: MT2 receptors mainly NREMS, whereas MT1 receptors REMS. © 2013 Elsevier B.V
Response to Letter to the Editor From Ville S. et al. About: “Eculizumab First” in the Management of Posttransplant Thrombotic Microangiopathy
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Effects of quetiapine and olanzapine in patients with psychosis and violent behavior: A pilot randomized, open-label, comparative study
No full textObjective: Patients suffering from psychosis are more likely than the general population to commit aggressive acts, but the therapeutics of aggressive behavior are still a matter of debate. Methods: This pilot randomized, open-label study compared the efficacy of quetiapine versus olanzapine in reducing impulsive and aggressive behaviors (primary endpoints) and psychotic symptoms (secondary endpoints) from baseline to days 1, 7, 14, 28, 42, 56, and 70, in 15 violent schizophrenic patients hospitalized in a maximum-security psychiatric hospital. Results: Quetiapine (525±45 mg) and olanzapine (18.5±4.8 mg) were both efficacious in reducing Impulsivity Rating Scale from baseline to day 70. In addition, both treatments reduced the Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale, and Clinical Global Impression Scale scores at day 70 compared to baseline, and no differences were observed between treatments. Moreover, quetiapine, but not olanzapine, yielded an improvement of depressive symptoms in the items "depression" in Brief Psychiatric Rating Scale and "blunted affect" in Positive and Negative Syndrome Scale. Modified Overt Aggression Scale scores were also decreased from baseline to the endpoint, but due to the limited number of patients, it was not possible to detect a significant difference. Conclusion: In this pilot study, quetiapine and olanzapine equally decreased impulsive and psychotic symptoms after 8 weeks of treatment. Double-blind, large studies are needed to confirm the validity of these two treatments in highly aggressive and violent schizophrenic patients. © 2014 Gobbi et al
Response to Letter to the Editor From Bouwmeester RN et al.: “Eculizumab in Postransplant TMA: Unproven Benefit.”
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Response to “A Caution Against the Use of C5B-9 Endothelial Assay to Support Eculizumab Therapy”
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Alcune note sui sistemi di monitoraggio di ticchiolatura e grado di attacco su melo dopo un triennio di esperienze
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