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ABSTRACT: Phytocannabinoid derivatives are among the several compounds found in the cannabis plant. The phytocannabinoid chemicals Δ9-tetrahydrocannabinol (THC) and cannabidiol are mostly responsible for the drug's behavioral effects. Chronic cannabis administration has been shown to disrupt circadian rhythms and reduce the duration of the deepest phase (stage N3) of nonrapid eye movement sleep. Cannabidiol is thought to be responsible for the disruption of the circadian rhythm, whereas THC is thought to be accountable for the changes in sleep architecture. The quality of one's sleep has a significant impact on cannabis abstinence or relapse. As a result, the diminished sleep-promoting efficiency of cannabis in chronic users, as well as the resulting sleep difficulties once cannabis use is stopped, may sabotage attempts to quit and raise the risk of relapse. In individuals with obstructive sleep apnea who do not complain about the treatment process known as continuous positive airway pressure, cannabinoids are one of the treatments being considered. In this regard, preclinical investigations have demonstrated that combining the agent oleamide and THC aids in the stabilization of respiration in all stages of sleep as well as the maintenance of autonomic stability during sleep. The synthetic THC dronabinol was found to lower the apnea-hypopnea index in a clinical investigation and is regarded safe for the short-term treatment of obstructive sleep apnea. Patients experiencing nightmares who had been diagnosed with posttraumatic stress disorder were given the synthetic endocannabinoid receptor agonist nabilone. When compared with a placebo, the chemical proved helpful in reducing the frequency of nightmares. It is worth noting that a single study that looked at the effects of cannabidiol on REM behavior disorder found that symptoms improved. Based on the available findings, cannabinoids can be used as an alternate treatment for various sleep disorders. However, additional research is needed to corroborate the conclusions of these investigations.
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Canabidiol , Canabinoides , Cannabis , Alucinógenos , Psiquiatria , Apneia Obstrutiva do Sono , Transtornos do Sono-Vigília , Analgésicos/uso terapêutico , Canabidiol/uso terapêutico , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Dronabinol/uso terapêutico , Humanos , Recidiva , Sono , Apneia Obstrutiva do Sono/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Transtornos do Sono-Vigília/etiologiaRESUMO
Hypocretins (Hcrt) 1 and 2 are two neuropeptides synthesized from neurons that are located in the perifornical area of the lateral hypothalamus. These neurons project diffusely throughout the central nervous system, and have been implicated in the generation and maintenance of wakefulness, as well as in critical physiological processes that occur during this behavioral state, such as motivation. The hypocretinergic projections towards the feline midbrain have not been studied before. Therefore, the aim of the present study was to analyze their relationship to the midbrain neurons, that are critically involved in the control of sleep and wakefulness. With this purpose, we examined the distribution of Hcrt1-positive fibers in the midbrain and pontomesencephalic area of the domestic cat (Felis catus), and their relationship with catecholaminergic and cholinergic neurons by means of single and double immunohistochemistry. Hcrtergic axons with distinctive varicosities and buttons were heterogeneously distributed, exhibiting different densities in distinct regions of the midbrain. High Hcrtergic fiber densities were observed in the periaqueductal gray, interpeduncular nucleus, locus coeruleus and cholinergic mesopontine regions. In addition, we studied in detail the Hcrtergic projection towards the dopaminergic nuclei of the midbrain. While very few Hcrtâ¯+â¯fibers were observed in the substantia nigra pars compacta, the highest density of Hcrtergic fibers was found in the dopaminergic ventral periaqueductal gray area (also called A10dc area); appositions between Hcrtergic terminals and dopaminergic somata and dendrites were observed within this area. Because this dopaminergic area has been involved in the control of wakefulness, the present anatomical data provides relevant support about the role of the Hcrtergic system in the generation of this behavioral state.
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Mesencéfalo/metabolismo , Neurônios/metabolismo , Orexinas/metabolismo , Vigília/fisiologia , Animais , Gatos , Imuno-Histoquímica , Masculino , Fibras Nervosas/metabolismo , Sono/fisiologiaRESUMO
Mesopontine and basal forebrain cholinergic neurons are involved in the control of behavioral states and cognitive functions. Animals treated with cholinergic muscarinic receptor antagonists display a dissociated state characterized by behavioral wakefulness (W) associated with high amplitude slow oscillations and spindles in the electroencephalogram (EEG), similar to those that occur during non-REM (NREM) sleep. Oscillations in the gamma frequency band (≈ 40 Hz) of the EEG also play a critical role during W and cognition. Hence, the present study was conducted to determine the effect of muscarinic antagonists on the EEG gamma band power and coherence. Five cats were implanted with electrodes in different cortices to monitor the EEG. The effects of atropine and scopolamine on power and coherence within the low gamma frequency band (30-45 Hz) from pairs of EEG recordings were analyzed and compared to gamma activity during sleep and W. Muscarinic antagonists induced a NREM sleep-like EEG profile that was accompanied by a large increase in gamma power and coherence. The values of gamma coherence were similar to that occurring during alert W (AW), and greater than in quiet W, NREM and REM sleep. We conclude that under atropine or scopolamine, functional interactions between cortical areas in the gamma frequency band remain high, as they are during AW. This significant functional connectivity at high frequency may explain why the animals remain awake in spite of the presence of slow waves and spindles.
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Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Eletroencefalografia , Antagonistas Muscarínicos/farmacologia , Animais , Atropina/farmacologia , Gatos , Eletrodos Implantados , Escopolamina/farmacologia , Sono/efeitos dos fármacos , Sono/fisiologia , Vigília/efeitos dos fármacos , Vigília/fisiologiaRESUMO
The effects of RO-600175, a selective 5-HT2C receptor agonist, were studied in adult rats implanted for chronic sleep recordings. Intraperitoneal administration of RO-600175 (4 mg/kg) during the light phase of the light-dark cycle significantly increased wakefulness and reduced slow wave sleep and rapid-eye-movement sleep during the first 2 h of the recording period. Direct infusion of RO-600175 into the dorsal raphe nucleus (4 mmol/l), laterodorsal tegmental nucleus (4 mmol/l), or horizontal limb of the diagonal band of Broca (4 mmol/l) also decreased rapid-eye-movement sleep. It is proposed that the activation of γ-aminobutyric acid-ergic cells located in the dorsal raphe nucleus, laterodorsal tegmental nucleus, and horizontal limb of the diagonal band of Broca is responsible, at least in part, for the effects of RO-600175 on rapid-eye-movement sleep. It is suggested that the increased wakefulness observed after systemic injection of the 5-HT2C receptor ligand could be partly related to the increased release of acetylcholine in the frontal cortex and hippocampus. However, additional studies are required to characterize the neurotransmitter systems responsible for the increase in wakefulness.
Assuntos
Etilaminas/administração & dosagem , Indóis/administração & dosagem , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/fisiologia , Eletrodos Implantados , Masculino , Microinjeções , Fotoperíodo , Ratos Wistar , Receptor 5-HT2C de Serotonina/metabolismo , Sono/fisiologia , Tegmento Mesencefálico/efeitos dos fármacos , Tegmento Mesencefálico/fisiologia , Vigília/fisiologiaRESUMO
The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of the lateral sector of the posterior hypothalamus and zona incerta. MCHergic neurons project throughout the central nervous system, including areas such as the dorsal (DR) and median (MR) raphe nuclei, which are involved in the control of sleep and mood. Major Depression (MD) is a prevalent psychiatric disease diagnosed on the basis of symptomatic criteria such as sadness or melancholia, guilt, irritability, and anhedonia. A short REM sleep latency (i.e., the interval between sleep onset and the first REM sleep period), as well as an increase in the duration of REM sleep and the density of rapid-eye movements during this state, are considered important biological markers of depression. The fact that the greatest firing rate of MCHergic neurons occurs during REM sleep and that optogenetic stimulation of these neurons induces sleep, tends to indicate that MCH plays a critical role in the generation and maintenance of sleep, especially REM sleep. In addition, the acute microinjection of MCH into the DR promotes REM sleep, while immunoneutralization of this peptide within the DR decreases the time spent in this state. Moreover, microinjections of MCH into either the DR or MR promote a depressive-like behavior. In the DR, this effect is prevented by the systemic administration of antidepressant drugs (either fluoxetine or nortriptyline) and blocked by the intra-DR microinjection of a specific MCH receptor antagonist. Using electrophysiological and microdialysis techniques we demonstrated also that MCH decreases the activity of serotonergic DR neurons. Therefore, there are substantive experimental data suggesting that the MCHergic system plays a role in the control of REM sleep and, in addition, in the pathophysiology of depression. Consequently, in the present report, we summarize and evaluate the current data and hypotheses related to the role of MCH in REM sleep and MD.
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Introducción: la depresión mayor (DM) es una enfermedad psiquiátrica frecuente, con importante morbilidad y una relación estrecha con el suicidio. Objetivo: hacer una puesta a punto de los avances en el estudio de la neurobiología de la DM, enfocándonos en el posible rol de la hormona concentradora de melanina (MCH) en esta patología. Metodología: revisión de la bibliografía con énfasis en nuestros propios trabajos originales. Resultados: la MCH es un neuromodulador peptídico sintetizado por neuronas del hipotálamo. Las neuronas MCHérgicas envían proyecciones hacia diversas regiones del sistema nervioso central, incluyendo las áreas vinculadas con la regulación de la vigilia y del sueño, así como a diversas estructuras del sistema límbico que participan en la regulación del humor. Aunque numerosos estudios han relacionado el sistema MCHérgico con el control de la homeostasis energética, hallazgos recientes han permitido señalar un rol de este sistema en los mecanismos de generación del sueño. A su vez, una convergencia de datos provenientes de diversos estudios sugiere que la MCH estaría involucrada en la fisiopatología de la DM. Nuestros propios estudios preclínicos tienden a indicar que la MCH promueve la generación del sueño REM y un estado tipo depresivo. Ambos efectos estarían siendo mediados a través de la modulación de la actividad de las neuronas serotoninérgicas del núcleo dorsal del rafe. Conclusiones: estudios preclínicos sugieren un rol protagónico del sistema MCHérgico en la fisiopatología de la depresión. Resta confirmar si esta afirmación es cierta en pacientes con DM. (AU)
Introduction: major depression disorder (MDD) is a common psychiatric condition, it has high morbility rates and is closely related to suicide.Objective: to provide an update in the study of the neurobiology of depression, focusing on the potential role of the melanin-concentrating hormone (MCH) in this condition.Method: a bibliographical review with an emphasis on our own original studies.Results: the melanin-concentrating hormone is a peptide neuromodulator syhthetized by neurones in the hypothalamus. MCHergic neurons send projection towards different areas in the central nervous system, including areas associated to the regulation of the sleep-wake cycle, as well as different structures in the limbic system that take part in the regulation of mood. In spite of several studies having proved the MCHergic system with the control of energetic homeostasis, recent findings have enabled to identify a role for this system in the sleep generator mechanisms. Similarly, data arising from several studies suggests that MCH would be involved in the major depression disorder. Our own preclinical studies tend to pint out the MCH promotes the generation of REM sleep and a type of depression. Apparently both effects would be mediated through the modulation of the activity on the serotoninergic neurons in the dorsal raphe nucleus.Conclusions: paraclinical studies suggest the leading role of the MCHergic system in the pathophysiology of depression. It is to be proved still, whether this affirmation is true for patients with major depression disorder.
Introdução: a depressão maior (DM) é uma enfermidade psiquiátrica frequente, com morbidade considerável e estreitamente relacionada com o suicídio.Objetivo: fazer uma atualização dos avanços no estudo da neurobiologia da DM, focando no possível papel do hormônio concentrador melanina (MCH) nesta patologia.Metodologia: revisão da bibliografia com ênfase em nossos trabalhos originais.Resultados: o MCH é um neuromodulador peptídico sintetizado pelos neurônios do hipotálamo. Os neurônios MCHérgicos enviam projeções a diversas regiões del sistema nervoso central, incluindo as áreas vinculadas com a regulação da vigília e do sono, bem como a diversas estruturas do sistema límbico que participam na regulação do humor. Embora numerosos estudos hajam relacionado o sistema MCHérgico com o controle da homeostase energética, descobrimentos recentes permitiram identificar um papel deste sistema nos mecanismos de geração do sono. Por outro lado, uma convergência de dados provenientes de diversos estudos sugere que o MCH estaria relacionado com a fisiopatologia da DM. Nossos estudos preclínicos tendem a indicar que o MCH promove a geração do sono REM e um estado tipo depressivo. Ambos efeitos estariam sendo mediados pela modulação da atividade dos neurônios serotoninérgicos do núcleo dorsal do rafe.Conclusões: estudos preclínicos sugerem um protagonismo do sistema MCHérgico na fisiopatologia da depressão. É necessário confirmar se esta afirmação é correta em pacientes com DM.
Assuntos
Depressão/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , NeurobiologiaRESUMO
Introducción: la depresión mayor (DM) es una enfermedad psiquiátrica frecuente, con importante morbilidad y una relación estrecha con el suicidio. Objetivo: hacer una puesta a punto de los avances en el estudio de la neurobiología de la DM, enfocándonos en el posible rol de la hormona concentradora de melanina (MCH) en esta patología. Metodología: revisión de la bibliografía con énfasis en nuestros propios trabajos originales. Resultados: la MCH es un neuromodulador peptídico sintetizado por neuronas del hipotálamo. Las neuronas MCHérgicas envían proyecciones hacia diversas regiones del sistema nervioso central, incluyendo las áreas vinculadas con la regulación de la vigilia y del sueño, así como a diversas estructuras del sistema límbico que participan en la regulación del humor. Aunque numerosos estudios han relacionado el sistema MCHérgico con el control de la homeostasis energética, hallazgos recientes han permitido señalar un rol de este sistema en los mecanismos de generación del sueño. A su vez, una convergencia de datos provenientes de diversos estudios sugiere que la MCH estaría involucrada en la fisiopatología de la DM. Nuestros propios estudios preclínicos tienden a indicar que la MCH promueve la generación del sueño REM y un estado tipo depresivo. Ambos efectos estarían siendo mediados a través de la modulación de la actividad de las neuronas serotoninérgicas del núcleo dorsal del rafe. Conclusiones: estudios preclínicos sugieren un rol protagónico del sistema MCHérgico en la fisiopatología de la depresión. Resta confirmar si esta afirmación es cierta en pacientes con DM...
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Humanos , Depressão/fisiopatologia , Neurobiologia , Transtorno Depressivo Maior/fisiopatologiaRESUMO
The effects of WAY-208466, a selective 5-HT6 receptor agonist on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. Systemic administration of WAY-208466 during the light phase of the light-dark cycle significantly increased wakefulness (W) and reduced slow wave sleep (SWS), REM sleep (REMS) and the number of REMS periods. Pretreatment with the selective 5-HT6 receptor antagonist RO-399885 prevented the effects of the 5-HT6 receptor agonist on W, SWS and REMS. Direct infusion of WAY-208466 into the dorsal raphe nucleus, locus coeruleus, basal forebrain (horizontal limb of the diagonal band of Broca) or laterodorsal tegmental nucleus specifically decreased REMS without significantly altering W or SWS. In all instances the REMS suppression was dependent upon the reduction of REMS periods. The finding that WAY-208466 increases extracellular γ-aminobutyric acid (GABA) levels in the rat frontal cortex tends to suggest that the neurotransmitter could be involved in the 5-HT6 receptor agonist-induced disruption of the sleep-wake cycle. However, further studies are needed to resolve this issue.
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Metilaminas/administração & dosagem , Piridinas/administração & dosagem , Núcleos da Rafe/efeitos dos fármacos , Receptores de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Animais , Masculino , Microinjeções/métodos , Ratos , Ratos WistarRESUMO
The melanin-concentrating hormone (MCH) is a 19 aminoacid peptide found in mammals predominantly in neurons located in the lateral hypothalamus and incerto-hypothalamic area. The biological function of MCH is mediated by two G-protein-coupled receptors known as MCHR1 and MCHR2, although the latter is expressed only in carnivores, primates and man. The MCHR1 couples to Gi, Gq and Go proteins, with Gi leading to the inhibition of both excitatory and inhibitory synaptic events. Within the central nervous system (CNS) MCH participates in a number of functions including sleep-wake behavior. In this respect, MCHergic neurons project widely throughout the CNS to brain regions involved in the regulation of behavioral states. MCHergic neurons are silent during wakefulness (W), increase their firing during slow wave sleep (SWS) and still more during REM sleep (REMS). Studies in knockout mice for MCH (MCH(-/-)) have shown a reduction in SWS and an increase of W during the light and the dark phase of the light-dark cycle. Moreover, in response to food deprivation a marked reduction in REMS time was observed in these animals. Conflicting effects on sleep variables have been reported in MCHR1(-/-) mice by different authors. The i.c.v. administration of MCH increases REMS and SWS in the rat. In addition, an enhancement of REMS has been described following the microinjection of the neuropeptide into the nucleus pontis oralis of the cat, while its infusion into the dorsal raphe nucleus (DR) and the basal forebrain (horizontal limb of the diagonal band of Broca) is followed by an increase of REMS and a reduction of W in the rat. Immunoneutralization of MCH in the DR augmented W and suppressed REMS in the rat, as did the s.c. injection of selective MCHR1 antagonists. The robust REMS-inducing effect of MCH is likely related to the deactivation of monoaminergic, orexinergic, glutamatergic, cholinergic (W-on) and GABAergic (REM-off) neurons involved in the generation of W and the inhibition of REMS. On the basis of preclinical studies, it can be proposed that selective MCHR1 receptor agonists could constitute potential therapeutic modalities in the arsenal of insomnia pharmacotherapy. Due to the lack of adequate animal models, the role of the MCHR2 on sleep is still unknown.
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Hormônios Hipotalâmicos/fisiologia , Melaninas/fisiologia , Hormônios Hipofisários/fisiologia , Sono/fisiologia , Vigília/fisiologia , Animais , Encéfalo/fisiologia , Gatos , Humanos , Hipotálamo/fisiologia , Camundongos , Neurotransmissores/fisiologia , Fases do Sono/fisiologiaRESUMO
Sleep-onset and maintenance insomnia is a common symptom in schizophrenic patients regardless of either their medication status (drug-naive or previously treated) or the phase of the clinical course (acute or chronic). Regarding sleep architecture, the majority of studies indicate that non-rapid eye movement (NREM), N3 sleep and REM sleep onset latency are reduced in schizophrenia, whereas REM sleep duration tends to remain unchanged. Many of these sleep disturbances in schizophrenia appear to be caused by abnormalities of the circadian system as indicated by misalignments of the endogenous circadian cycle and the sleep-wake cycle. Circadian disruption, sleep onset insomnia and difficulties in maintaining sleep in schizophrenic patients could be partly related to a presumed hyperactivity of the dopaminergic system and dysfunction of the GABAergic system, both associated with core features of schizophrenia and with signaling in sleep and wake promoting brain regions. Since multiple neurotransmitter systems within the CNS can be implicated in sleep disturbances in schizophrenia, the characterization of the neurotransmitter systems involved remains a challenging dilemma.
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Ritmo Circadiano/fisiologia , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Transtornos do Sono-Vigília/etiologia , Sono/fisiologia , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Doença Crônica , Humanos , Melatonina/análogos & derivados , Melatonina/uso terapêutico , Esquizofrenia/complicações , Transtornos do Sono-Vigília/tratamento farmacológicoRESUMO
The ventrolateral preoptic area (VLPO) has been recognized as one of the key structures responsible for the generation of non-REM (NREM) sleep. The melanin-concentrating hormone (MCH)-containing neurons, which are located in the lateral hypothalamus and incerto-hypothalamic area, project widely throughout the central nervous system and include projections to the VLPO. The MCH has been associated with the central regulation of feeding and energy homeostasis. In addition, recent findings strongly suggest that the MCHergic system promotes sleep. The aim of the present study was to determine if MCH generates sleep by regulating VLPO neuronal activity. To this purpose, we characterized the effect of unilateral and bilateral microinjections of MCH into the VLPO on sleep and wakefulness in the rat. Unilateral administration of MCH into the VLPO and adjacent dorsal preoptic area did not modify sleep. On the contrary, bilateral microinjections of MCH (100 ng) into these areas significantly increased light sleep (LS, 39.2±4.8 vs. 21.6±2.5 min, P<0.05) and total NREM sleep (142.4±23.2 vs. 86.5±10.5 min, P<0.05) compared to control (saline) microinjections. No effect was observed on REM sleep. We conclude that MCH administration into the VLPO and adjacent dorsal lateral preoptic area promotes the generation of NREM sleep.
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Hormônios Hipotalâmicos/fisiologia , Melaninas/fisiologia , Hormônios Hipofisários/fisiologia , Área Pré-Óptica/fisiologia , Sono REM , Animais , Hormônios Hipotalâmicos/administração & dosagem , Masculino , Melaninas/administração & dosagem , Microinjeções , Hormônios Hipofisários/administração & dosagem , Ratos , Ratos WistarRESUMO
The effects of SB-269970, a selective 5-HT7 receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The 5-HT7 receptor ligand was microinjected into the horizontal limb of the diagonal band of Broca (HDB) and the laterodorsal tegmental nucleus (LDT) during the light period of the 12-h light/12-h dark cycle. For comparative purposes the compound was administered systemically and, in addition, injected directly into the dorsal raphe nucleus (DRN). Microinjection of SB-269970 into the HDB and the DRN induced a significant reduction of rapid-eye-movement sleep (REMS). Similar effects were observed after systemic administration of the 5-HT7 receptor antagonist. On the other hand, local infusion of the compound into the LDT provoked the opposite effect. It is proposed that the deactivation of GABAergic cells located in the HDB, DRN and LDT is responsible for the changes induced by SB-269970 on REM sleep values. It is suggested that the antidepressant effect of the 5-HT7 receptor antagonist could partly depend on the involvement of neuronal systems located in the DRN and the HDB.
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Tronco Encefálico/efeitos dos fármacos , Fenóis/farmacologia , Prosencéfalo/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Sono REM/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Tronco Encefálico/fisiologia , Masculino , Microinjeções , Prosencéfalo/fisiologia , Ratos , Ratos WistarRESUMO
AIMS: To examine the effects of bilateral microinjection of melanin-concentrating hormone (MCH) 50 and 100 ng into the horizontal limb of the diagonal band of Broca (HDB) on sleep variables during the light phase of the light-dark cycle of the rat. MAIN METHODS: Male Wistar rats were implanted for chronic sleep recordings. In addition, a guide cannula was implanted above the right and left HDB. Following the microinjection of MCH or control solution the electroencephalogram and the electromyogram were recorded for 6 h. Data was collected and classified as either wakefulness (W), light sleep, slow wave sleep (SWS) or REM sleep (REMS). Latencies for SWS and REMS, as well as the number of REM periods and the mean duration of REM episodes were also determined. KEY FINDINGS: MCH 50 and 100 ng significantly decreased W during the first 2-h of recording. Moreover, MCH 100 ng significantly reduced REMS latency and increased REMS time during the first 2-h block of the recording, due to an increase in the number of REM periods. SIGNIFICANCE: Our findings tend to suggest that the basal forebrain participates in the effects of MCH on W and REMS through the deactivation of cholinergic, glutamatergic and γ-aminobutyric acid (GABA)-ergic cells.
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Hormônios Hipotalâmicos/farmacologia , Melaninas/farmacologia , Hormônios Hipofisários/farmacologia , Prosencéfalo/metabolismo , Sono REM/efeitos dos fármacos , Vigília/efeitos dos fármacos , Acetilcolina/metabolismo , Animais , Relação Dose-Resposta a Droga , Eletroencefalografia , Eletromiografia , Ácido Glutâmico/metabolismo , Hormônios Hipotalâmicos/administração & dosagem , Masculino , Melaninas/administração & dosagem , Microinjeções , Hormônios Hipofisários/administração & dosagem , Ratos , Ratos Wistar , Ácido gama-Aminobutírico/metabolismoRESUMO
Neurons containing the neuropeptide melanin-concentrating hormone (MCH) are mainly located in the lateral hypothalamus and the incerto-hypothalamic area, and have widespread projections throughout the brain. While the biological functions of this neuropeptide are exerted in humans through two metabotropic receptors, the MCHR1 and MCHR2, only the MCHR1 is present in rodents. Recently, it has been shown that the MCHergic system is involved in the control of sleep. We can summarize the experimental findings as follows: (1) The areas related to the control of sleep and wakefulness have a high density of MCHergic fibers and receptors. (2) MCHergic neurons are active during sleep, especially during rapid eye movement (REM) sleep. (3) MCH knockout mice have less REM sleep, notably under conditions of negative energy balance. Animals with genetically inactivated MCHR1 also exhibit altered vigilance state architecture and sleep homeostasis. (4) Systemically administered MCHR1 antagonists reduce sleep. (5) Intraventricular microinjection of MCH increases both slow wave sleep (SWS) and REM sleep; however, the increment in REM sleep is more pronounced. (6) Microinjection of MCH into the dorsal raphe nucleus increases REM sleep time. REM seep is inhibited by immunoneutralization of MCH within this nucleus. (7) Microinjection of MCH in the nucleus pontis oralis of the cat enhances REM sleep time and reduces REM sleep latency. All these data strongly suggest that MCH has a potent role in the promotion of sleep. Although both SWS and REM sleep are facilitated by MCH, REM sleep seems to be more sensitive to MCH modulation.
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The effects of the selective 5-HT(3) receptor agonist m-chlorophenylbiguanide (m-CPBG), and of the NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate)/kainate antagonists AP-5 [(±)-2-amino-5-phosphono-pentanoic acid] and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), respectively, were studied in adult male Wistar rats implanted for chronic sleep recordings. The compounds were microinjected directly into the dorsal raphe nucleus (DRN) during the light period of the 12-h light/12-h dark cycle. Infusion of m-CPBG (2 and 4mM) into the DRN induced a significant reduction of rapid-eye-movement sleep (REMS) and of the number of REM periods. Local infusion of AP-5 (0.5-1 mM) and CNQX (2 mM) significantly increased slow wave sleep (SWS). Pretreatment with AP-5 (0.5 mM) or CNQX (0.5 mM) antagonized the m-CPBG-induced suppression of REMS. It is proposed that the reduction of REMS after microinjection of m-CPBG into de DRN is related to the activation of glutamatergic interneurons that express the 5-HT(3) receptor and make synaptic contacts with serotonergic cells. The resultant increase of serotonin release at postsynaptic sites involved in the induction of REMS would provoke the suppression of the behavioral state. Our findings provide, in addition, new details concerning the pharmacology of DRN serotonergic neurons in the rat that may become relevant to the development of drugs for enhancing cortical and subcortical serotonergic neurotransmission.
Assuntos
Biguanidas/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Agonistas do Receptor 5-HT3 de Serotonina/farmacologia , Sono REM/efeitos dos fármacos , 2-Amino-5-fosfonovalerato/farmacologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Eletromiografia/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , N-Metilaspartato/metabolismo , Núcleos da Rafe/metabolismo , Núcleos da Rafe/fisiologia , Ratos , Ratos Wistar , Receptores de Ácido Caínico/antagonistas & inibidores , Receptores 5-HT3 de Serotonina , Sono/efeitos dos fármacos , Sono/fisiologia , Privação do Sono , Sono REM/fisiologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismoRESUMO
Based on electrophysiological, neurochemical, genetic and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) functions predominantly to promote wakefulness (W) and to inhibit REM (rapid eye movement) sleep (REMS). Yet, under certain circumstances the neurotransmitter contributes to the increase in sleep propensity. Most of the serotonergic innervation of the cerebral cortex, amygdala, basal forebrain (BFB), thalamus, preoptic and hypothalamic areas, raphe nuclei, locus coeruleus and pontine reticular formation comes from the dorsal raphe nucleus (DRN). The 5-HT receptors can be classified into at least seven classes, designated 5-HT(1-7). The 5-HT(1A) and 5-HT(1B) receptor subtypes are linked to the inhibition of adenylate cyclase, and their activation evokes a membrane hyperpolarization. The actions of the 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptor subtypes are mediated by the activation of phospholipase C, with a resulting depolarization of the host cell. The 5-HT(3) receptor directly activates a 5-HT-gated cation channel which leads to the depolarization of monoaminergic, aminoacidergic and cholinergic cells. The primary signal transduction pathway of 5-HT(6) and 5-HT(7) receptors is the stimulation of adenylate cyclase which results in the depolarization of the follower neurons. Mutant mice that do not express 5-HT(1A) or 5-HT(1B) receptor exhibit greater amounts of REMS than their wild-type counterparts, which could be related to the absence of a postsynaptic inhibitory effect on REM-on neurons of the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT). 5-HT(2A) and 5-HT(2C) receptor knock-out mice show a significant increase of W and a reduction of slow wave sleep (SWS) which has been ascribed to the increase of catecholaminergic neurotransmission involving mainly the noradrenergic and dopaminergic systems. Sleep variables have been characterized, in addition, in 5-HT(7) receptor knock-out mice; the mutants spend less time in REMS that their wild-type counterparts. Direct infusion of the 5-HT(1A) receptor agonists 8-OH-DPAT and flesinoxan into the DRN significantly enhances REMS in the rat. In contrast, microinjection of the 5-HT(1B) (CP-94253), 5-HT(2A/2C) (DOI), 5-HT(3) (m-chlorophenylbiguanide) and 5-HT(7) (LP-44) receptor agonists into the DRN induces a significant reduction of REMS. Systemic injection of full agonists at postsynaptic 5-HT(1A) (8-OH-DPAT, flesinoxan), 5-HT(1B) (CGS 12066B, CP-94235), 5-HT(2C) (RO 60-0175), 5-HT(2A/2C) (DOI, DOM), 5-HT(3) (m-chlorophenylbiguanide) and 5-HT(7) (LP-211) receptors increases W and reduces SWS and REMS. Of note, systemic administration of the 5-HT(2A/2C) receptor antagonists ritanserin, ketanserin, ICI-170,809 or sertindole at the beginning of the light period has been shown to induce a significant increase of SWS and a reduction of REMS in the rat. Wakefulness was also diminished in most of these studies. Similar effects have been described following the injection of the selective 5-HT(2A) receptor antagonists volinanserin and pruvanserin and of the 5-HT(2A) receptor inverse agonist nelotanserin in rodents. In addition, the effects of these compounds have been studied on the sleep electroencephalogram of subjects with normal sleep. Their administration was followed by an increase of SWS and, in most instances, a reduction of REMS. The administration of ritanserin to poor sleepers, patients with chronic primary insomnia and psychiatric patients with a generalized anxiety disorder or a mood disorder caused a significant increase in SWS. The 5-HT(2A) receptor inverse agonist APD-125 induced also an increase of SWS in patients with chronic primary insomnia. It is known that during the administration of benzodiazepine (BZD) hypnotics to patients with insomnia there is a further reduction of SWS and REMS, whereas both variables tend to remain decreased during the use of non-BZD derivatives (zolpidem, zopiclone, eszopiclone, zaleplon). Thus, the association of 5-HT(2A) antagonists or 5-HT(2A) inverse agonists with BZD and non-BZD hypnotics could be a valid alternative to normalize SWS in patients with primary or comorbid insomnia.
Assuntos
Serotonina/fisiologia , Sono/fisiologia , Vigília/fisiologia , Animais , Encéfalo/fisiologia , Humanos , Camundongos , Núcleos da Rafe/fisiologia , Ratos , Receptores de Serotonina/fisiologia , Transtornos do Sono-Vigília/fisiopatologia , Sono REM/fisiologiaRESUMO
The effects of the 5-HT6 receptor antagonists SB-399885 (2.5, 5 and 10 mg/kg) and RO-4368554 (2.5, 5 and 10 mg/kg) and of the 5-HT(2A) receptor antagonist EMD 281014 (2.5, 5 and 10 mg/kg) were studied in rats implanted for chronic sleep procedures. Administration of 10 mg/kg SB-399885, i.p., to rats 2 h after the beginning of the light phase of the light-dark cycle caused a significant increase of wakefulness (W) and a reduction of slow wave sleep (SWS), REM sleep (REMS) and the number of REM periods during 6-h recording sessions. Light sleep was increased after the whole range of doses. The increase of W and reduction of SWS and REMS occurred predominantly during the first 2-h period whereas light sleep was augmented over the first and the second 2-h recording periods. Injection of RO-4368554 (10 mg/kg, i.p.) 2 h after the beginning of the light period significantly increased W and reduced SWS and REMS during the first 2-h recording period. Administration of EMD 281014 (10 mg/kg, i.p.) during the light phase significantly increased SWS and reduced light sleep during 6-h sessions. REMS and the number of REM period were reduced with the entire range of doses. The reduction of REMS and light sleep and the increase of SWS occurred predominantly during the first and the second 2-h of recording, respectively. Injection of SB-399885 (10 mg/kg, i.p.) 2 h after the beginning of the dark period induced a significant reduction of REMS during the first 2-h of recording. In contrast, RO-4368554 did not modify values corresponding to sleep variables during the dark period. Treatment with EMD 281014 (2.5-10 mg/kg, i.p.) during the dark phase significantly increased SWS during the second 2-h period. Our study supports the proposal that blockade of postsynaptic 5-HT6 receptors with systemic administration of SB-399885 and RO-4368554 increases W and reduces SWS and REMS during the light phase of the sleep-wake cycle. SB-399885 also induces a suppression of REMS during the dark period. It was confirmed, in addition, that administration of the 5-HT(2A) receptor antagonist EMD 281014 enhances SWS during both phases of the light-dark cycle in the rat.
Assuntos
Indóis/farmacologia , Piperazinas/farmacologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptores de Serotonina/fisiologia , Sono/efeitos dos fármacos , Sulfonamidas/farmacologia , Vigília/efeitos dos fármacos , Análise de Variância , Animais , Eletroencefalografia , Masculino , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologia , Sono/fisiologia , Vigília/fisiologiaRESUMO
Hypothalamic neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator exert a positive control over energy homeostasis, inducing feeding and decreasing metabolism. Recent studies have shown also that this system plays a role in the generation and/or maintenance of sleep. MCHergic neurons project to the serotonergic dorsal raphe nucleus (DR), a neuroanatomical structure involved in several functions during wakefulness (W), and in the regulation of rapid-eye movements (REM) sleep. Recently, we determined the effect of MCH microinjected into the DR on sleep variables in the rat. MCH produced a marked increment of REM sleep, whereas slow wave sleep (SWS) showed only a moderate increase. In the present study, we analyze the effect of immunoneutralization of MCH in the DR on sleep and W in the rat. Compared to the control solution, microinjections of anti-MCH antibodies (1/100 solution in 0.2 µl) induced a significant increase in REM sleep latency (31.2±7.1 vs. 84.2±24.8 min, p<0.05) and a decrease of REM sleep time (37.8±5.4 vs. 17.8±2.9 min, p<0.05) that was related to the reduction in the number of REM sleep episodes. In addition, there was an increase of total W time (49.8±4.6 vs. 72.0±5.7 min, p<0.01). Light sleep and SWS remained unchanged. The intra-DR administration of a more diluted solution of anti-MCH antibodies (1/500) or rabbit pre-immune serum did not modify neither W nor REM sleep variables. Our findings strongly suggest that MCH released in the DR facilitates the occurrence of REM sleep.
Assuntos
Hormônios Hipotalâmicos/metabolismo , Melaninas/metabolismo , Hormônios Hipofisários/metabolismo , Núcleos da Rafe/metabolismo , Sono REM/fisiologia , Vigília/fisiologia , Animais , Hormônios Hipotalâmicos/farmacologia , Masculino , Melaninas/farmacologia , Microinjeções , Hormônios Hipofisários/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Wistar , Sono/fisiologiaRESUMO
Based on electrophysiological, neurochemical, genetic and neuropharmacological approaches it is currently accepted that serotonin (5-HT) functions to promote waking (W) and to inhibit rapid-eye movement sleep (REMS). The serotonin-containing neurons of the dorsal raphe nucleus (DRN) provide part of the serotonergic innervation of the telencephalon, diencephalon, mesencephalon and rhombencephalon of laboratory animals and man. The DRN has been subdivided into several clusters on the basis of differences in cellular morphology, expression of other neurotransmitters and afferent and efferent connections. These differences among subpopulations of 5-HT neurons may have important implications for neural mechanisms underlying 5-HT modulation of sleep and waking. The DRN contains 5-HT and non-5-HT neurons. The latter express a variety of substances including dopamine, γ-aminobutyric acid (GABA) and glutamate. In addition, nitric oxide and a number of neuropeptides have been characterized in the DRN. Available evidence tends to indicate that non-5-HT cells contribute to the regulation of the activity of 5-HT neurons during the sleep-wake cycle through local circuits and/or their mediation of the effects of afferent inputs. Mutant mice that do not express 5-HT(1A) or 5-HT(1B) receptor exhibit greater amounts of REMS than their wild-type couterparts. 5-HT(2A) and 5-HT(2C) receptor knockout mice show a significant increase of W and a reduction of slow wave sleep that is related, at least in part, to the increased release of norepinephrine and dopamine. A normal circadian sleep pattern is observed in 5-HT(7) receptor knockout mice; however, the mutants spend less time in REMS. Local microinjection of 5-HT(1B), 5-HT(2A/2C), 5-HT(3) and 5-HT(7) receptor agonists into the DRN selectively suppresses REMS in the rat. In contrast, microinjection of 5-HT(1A) receptor agonists promotes REMS. Similarly, local administration of the melanin-concentrating hormone or the GABA(A) receptor agonist muscimol produces an increase of REMS in the rat. Presently, there are no data on the effect of local infusion into the DRN of noradrenergic, dopaminergic, histaminergic, orexinergic and cholinergic agonists on sleep variables in laboratory animals.