1,721,091 research outputs found
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
Differential function of melatonin MT1 and MT2 receptors in REM and NREM sleep
Full text linkThe 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
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
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
Hypnotic Effects of Melatonergic Compounds Measured in Mice or Rats
No full textMelatonin is a pleiotropic compound mostly acting through its two G protein-coupled receptors named MT1 and MT2 and known for its role in regulating the sleep/wake cycle and circadian rhythms. Although this is common belief, there has been long debate in the scientific community on whether melatonin or melatonergic compounds are endowed with hypnotic effects. One of the reasons for this debate relied on contrasting findings in the literature in part due to non-standardized methods across studies in examining at preclinical level the effect of melatonin or melatonergic compounds on the sleep/wake cycle. Here, we describe a method in mice and rats to evaluate the effect of melatonin or melatonergic compounds on the different stages of the sleep/wake cycle, providing details concerning the administration of the drug and the analytical procedure for scoring the electroencephalogram/electromyogram (EEG/EMG) recording
Wellness assessment of alzheimer’s patients in an instrumented health-care facility
Full text linkWellness assessment refers to the evaluation of physical, mental, and social well-being. This work explores the possibility of applying technological tools to assist clinicians and professionals to improve the quality of life of people through continuous monitoring of their wellness. The contribution of this paper is manifold: a coarse-grained localization system is responsible for monitoring and collecting data related to patients, while a novel wellness assessment methodology is proposed to extract quantitative indicators related to the well-being of patients from the collected data. The proposed system has been installed at “Il Paese Ritrovato”, an innovative health-care facility for Alzheimer’s in Monza, Italy; first satisfactory results have been obtained, and the dataset shows great potential for several applications
The psychopharmacology of aggressive behavior: A translational approach: Part 1: Neurobiology
No full textPatients with mental disorders are at an elevated risk for developing aggressive behavior. In the last 19 years, the psychopharmacological treatment of aggression has changed dramatically because of the introduction of atypical antipsychotics into the market and the increased use of anticonvulsants and lithium in the treatment of aggressive patients.Using a translational medicine approach, this review (part 1 of 2) examines the neurobiology of aggression, discussing the major neurotransmitter systems implicated in its pathogenesis, namely, serotonin, glutamate, norepinephrine, dopamine, and γ-aminobutyric acid, and also their respective receptors. The preclinical and clinical pharmacological studies concerning the role of these neurotransmitters have been reviewed, as well as research using transgenic animal models. The complex interaction among these neurotransmitters occurs at the level of brain areas and neural circuits such as the orbitoprefrontal cortex, anterior cortex, amygdala, hippocampus, periaqueductal gray, and septal nuclei, where the receptors of these neurotransmitters are expressed. The neurobiological mechanism of aggression is important to understand the rationale for using atypical antipsychotics, anticonvulsants, and lithium in treating aggressive behavior. Further research is necessary to establish how these neurotransmitter systems interact with brain circuits to control aggressive behavior at the intracellular level.© 2012 by Lippincot t Williams & Wilkins
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
Drugs for insomnia beyond benzodiazepines: Pharmacology, clinical applications, and discovery
No full textAlthough the GABAergic benzodiazepines (BZDs) and Z-drugs (zolpidem, zopiclone, and zaleplon) are FDA-approved for insomnia disorders with a strong evidence base, they have many side effects, including cognitive impairment, tolerance, rebound insomnia upon discontinuation, car accidents/falls, abuse, and dependence liability. Consequently, the clinical use of off-label drugs and novel drugs that do not target the GABAergic system is increasing. The purpose of this review is to analyze the neurobiological and clinical evidence of pharmacological treatments of insomnia, excluding the BZDs and Z-drugs. We analyzed the melatonergic agonist drugs, agomelatine, prolongedrelease melatonin, ramelteon, and tasimelteon; the dual orexin receptor antagonist suvorexant; the modulators of the a2d subunit of voltage-sensitive calcium channels, gabapentin and pregabalin; the H1 antagonist, low-dose doxepin; and the histamine and serotonin receptor antagonists, amitriptyline, mirtazapine, trazodone, olanzapine, and quetiapine. The pharmacology and mechanism of action of these treatments and the evidence-base for the use of these drugs in clinical practice is outlined alongwith novel pipelines. There is evidence to recommend suvorexant and low-dose doxepin for sleep maintenance insomnia; there is also sufficient evidence to recommend ramelteon for sleep onset insomnia. Although there is limited evidence for the use of the quetiapine, trazodone, mirtazapine, amitriptyline, pregabalin, gabapentin, agomelatine, and olanzapine as treatments for insomnia disorder, these drugs may improve sleep while successfully treating comorbid disorders, with a different side effect profile than the BZDs and Z-drugs. The unique mechanism of action of each drug allows for a more personalized and targeted medical management of insomnia
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