DOAJ (DOAJ: Directory of Open Access Journals), Sep 1, 2018
Sleep is a reversible state of lack of consciousness and response to the environment that is acco... more Sleep is a reversible state of lack of consciousness and response to the environment that is accompanied by important physiological adjustments. This is subdivided in two behavioral states, REM sleep and non-REM sleep (NREM).There are pathological processes that manifest mainly during sleep. Within these, parasomnias are defined as the pathologies in which undesirable behaviors occur during sleep. The parasomnias are subdivided into those that occur during NREM and REM sleep.Among NREM-parasomnias, somnambulism (sleep-walking) is highlighted, which is characterized by complex motor behavior during sleep, mainly affecting children. Another important parasomnia is the night terror, which is a dramatic event that represents a partial awakening during deep sleep, which is accompanied by an important autonomic activation.Among REM-parasomnias, the most important is REM sleep behavior disorder. This is characterized by the absence of the muscular atony that is characteristic of this behavioral state. This determines that patients act their own dreams (which mainly occur during REM sleep) and can result in injuries of diverse entity. This parasomnia is associated with neurodegenerative diseases such as Parkinson's disease.Since sleep disorders in general, and parasomnias in particular, are relatively unknown disorders in our medical system, in this work we made a state of the art of this subject.
Several drug classes are widely prescribed when difficulties with sleep induction or sleep mainte... more Several drug classes are widely prescribed when difficulties with sleep induction or sleep maintenance occur, as is the case in patients with an insomnia disorder. These include the benzodiazepine and non-benzodiazepine receptor allosteric modulators, the melanin receptor agonist ramelteon, low-dose doxepin, and the orexin receptor antagonist suvorexant. Benzodiazepines are often less than satisfactory, since they are known to produce reductions in both N3 sleep and rapid-eye movement (REM) sleep. Similarly, low-dose doxepin has been associated with a reduction in REM sleep. Initially, it was shown that the non-selective serotonin 5-HT2A/2C receptor antagonists’ ritanserin, ketanserin, seganserin, and ICI-169,369 increase N3 sleep in subjects with normal sleep. Ritanserin produced also an increase of N3 sleep in poor sleepers, patients with a chronic insomnia disorder, and psychiatric patients with a generalized anxiety disorder or a mood disorder. More recent evidence indicates that the selective 5-HT2A receptor antagonist volinanserin and the 5-HT2A receptor inverse agonists’ nelotanserin and pimavanserin significantly increase N3 sleep in subjects with normal sleep. Nelotanserin was also shown to augment N3 sleep in patients with a chronic insomnia disorder. N2 sleep tended to decrease in most of these studies, while REM sleep showed no significant changes. The present review which summarizes these findings is the basis for a proposal for a new therapeutic strategy. It is proposed that the co-administration of a selective 5-HT2A receptor antagonist or inverse agonist along with a hypnotic drug could be a valid clinical strategy for normalizing sleep induction and maintenance and for promoting N3 sleep in patients with an insomnia disorder.
Depression is a mood disorder affecting emotional, somatic, and cognitive domains. The efficacy o... more Depression is a mood disorder affecting emotional, somatic, and cognitive domains. The efficacy of the antidepressant therapies is generally acceptable; however, unpleasant or adverse effects, delayed onset of action, and unresponsive patients continue to be the most common problem in the psychiatric practice. Under these circumstances, the recent implication of the hypothalamic neuropeptide melanin-concentrating hormone (MCH) in the regulation of emotion and mood has offered a great opportunity to study this neuropeptidergic system in the neural bases of depression and its treatment.
RATIONALE The medical uses of cannabidiol (CBD), a constituent of the Cannabis sativa, have accel... more RATIONALE The medical uses of cannabidiol (CBD), a constituent of the Cannabis sativa, have accelerated the legal and social acceptance for CBD-based medications but has also given the momentum for questioning whether the long-term use of CBD during the early years of life may induce adverse neurobiological effects in adulthood, including sleep disturbances. Given the critical window for neuroplasticity and neuro-functional changes that occur during stages of adolescence, we hypothesized that CBD might influence the sleep-wake cycle in adult rats after their exposure to CBD during the adolescence. OBJECTIVES Here, we investigated the effects upon behavior and neural activity in adulthood after long-term administrations of CBD in juvenile rats. METHODS We pre-treated juvenile rats with CBD (5 or 30 mg/Kg, daily) from post-natal day (PND) 30 and during 2 weeks. Following the treatments, the sleep-wake cycle and NeuN expression was analyzed at PND 80. RESULTS We found that systemic injections of CBD (5 or 30 mg/Kg, i.p.) given to adolescent rats (post-natal day 30) for 14 days increased in adulthood the wakefulness and decreased rapid eye movement sleep during the lights-on period whereas across the lights-off period, wakefulness was diminished and slow wave sleep was enhanced. In addition, we found that adult animals that received CBD during the adolescence displayed disruptions in sleep rebound period after total sleep deprivation. Finally, we determined how the chronic administrations of CBD during the adolescence affected in the adulthood the NeuN expression in the suprachiasmatic nucleus, a sleep-related brain region. CONCLUSIONS Our findings are relevant for interpreting results of adult rats that were chronically exposed to CBD during the adolescence and provide new insights into how CBD may impact the sleep-wake cycle and neuronal activity during developmental stages.
5-HT2A Receptors in the Central Nervous System, 2018
Several agents have been shown to improve sleep induction and/or maintenance in patients with pri... more Several agents have been shown to improve sleep induction and/or maintenance in patients with primary or comorbid insomnia. These include benzodiazepine and non-benzodiazepine receptor allosteric modulators, melatonin and the melatonin receptor agonist ramelteon, low dose doxepin, and suvorexant. However, benzodiazepines induce a further reduction of N3 sleep [slow wave sleep (SWS) or delta sleep] and rapid-eye-movement sleep (REMS), whereas values corresponding to these variables remain decreased during non-benzodiazepine, melatonin, ramelteon or low-dose doxepin administration. By contrast, suvorexant increases REMS. There is evidence indicating that non-selective (ritanserin, ketanserin, sertindole, ICI-170809, ICI-169369, RP-62203, SR-46349B) and selective (volinanserin, pruvanserin, eplivanserin) 5-HT2A receptor antagonists, as well as 5-HT2A receptor inverse agonists (nelotanserin, pimavanserin) increase SWS in laboratory animals and N3 sleep in subjects with normal sleep and/or patients with an insomnia disorder. Thus, the association of a selective 5-HT2A receptor antagonist or a 5-HT2A receptor inverse agonist with a hypnotic drug could be a valid alternative to normalize N3 sleep in patients with an insomnia complaint.
Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized in the... more Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized in the postero-lateral hypothalamus and incerto-hypothalamic area. These neurons project diffusely throughout the central nervous system and have been implicated in critical physiological processes, such as sleep. Unlike rodents, in the order carnivora as well as in humans, MCH exerts its biological functions through two receptors: MCHR-1 and MCHR-2. Hence, the cat is an optimal animal to model MCHergic functions in humans. In the present study, we examined the distribution of MCH-positive fibers in the brainstem of the cat. MCHergic axons with distinctive varicosities and boutons were heterogeneously distributed, exhibiting different densities in distinct regions of the brainstem. High density of MCHergic fibers was found in the dorsal raphe nucleus, the laterodorsal tegmental nucleus, the periaqueductal gray, the pendunculopontine tegmental nucleus, the locus coeruleus and the prepositus hyp...
DOAJ (DOAJ: Directory of Open Access Journals), Sep 1, 2018
Sleep is a reversible state of lack of consciousness and response to the environment that is acco... more Sleep is a reversible state of lack of consciousness and response to the environment that is accompanied by important physiological adjustments. This is subdivided in two behavioral states, REM sleep and non-REM sleep (NREM).There are pathological processes that manifest mainly during sleep. Within these, parasomnias are defined as the pathologies in which undesirable behaviors occur during sleep. The parasomnias are subdivided into those that occur during NREM and REM sleep.Among NREM-parasomnias, somnambulism (sleep-walking) is highlighted, which is characterized by complex motor behavior during sleep, mainly affecting children. Another important parasomnia is the night terror, which is a dramatic event that represents a partial awakening during deep sleep, which is accompanied by an important autonomic activation.Among REM-parasomnias, the most important is REM sleep behavior disorder. This is characterized by the absence of the muscular atony that is characteristic of this behavioral state. This determines that patients act their own dreams (which mainly occur during REM sleep) and can result in injuries of diverse entity. This parasomnia is associated with neurodegenerative diseases such as Parkinson's disease.Since sleep disorders in general, and parasomnias in particular, are relatively unknown disorders in our medical system, in this work we made a state of the art of this subject.
Several drug classes are widely prescribed when difficulties with sleep induction or sleep mainte... more Several drug classes are widely prescribed when difficulties with sleep induction or sleep maintenance occur, as is the case in patients with an insomnia disorder. These include the benzodiazepine and non-benzodiazepine receptor allosteric modulators, the melanin receptor agonist ramelteon, low-dose doxepin, and the orexin receptor antagonist suvorexant. Benzodiazepines are often less than satisfactory, since they are known to produce reductions in both N3 sleep and rapid-eye movement (REM) sleep. Similarly, low-dose doxepin has been associated with a reduction in REM sleep. Initially, it was shown that the non-selective serotonin 5-HT2A/2C receptor antagonists’ ritanserin, ketanserin, seganserin, and ICI-169,369 increase N3 sleep in subjects with normal sleep. Ritanserin produced also an increase of N3 sleep in poor sleepers, patients with a chronic insomnia disorder, and psychiatric patients with a generalized anxiety disorder or a mood disorder. More recent evidence indicates that the selective 5-HT2A receptor antagonist volinanserin and the 5-HT2A receptor inverse agonists’ nelotanserin and pimavanserin significantly increase N3 sleep in subjects with normal sleep. Nelotanserin was also shown to augment N3 sleep in patients with a chronic insomnia disorder. N2 sleep tended to decrease in most of these studies, while REM sleep showed no significant changes. The present review which summarizes these findings is the basis for a proposal for a new therapeutic strategy. It is proposed that the co-administration of a selective 5-HT2A receptor antagonist or inverse agonist along with a hypnotic drug could be a valid clinical strategy for normalizing sleep induction and maintenance and for promoting N3 sleep in patients with an insomnia disorder.
Depression is a mood disorder affecting emotional, somatic, and cognitive domains. The efficacy o... more Depression is a mood disorder affecting emotional, somatic, and cognitive domains. The efficacy of the antidepressant therapies is generally acceptable; however, unpleasant or adverse effects, delayed onset of action, and unresponsive patients continue to be the most common problem in the psychiatric practice. Under these circumstances, the recent implication of the hypothalamic neuropeptide melanin-concentrating hormone (MCH) in the regulation of emotion and mood has offered a great opportunity to study this neuropeptidergic system in the neural bases of depression and its treatment.
RATIONALE The medical uses of cannabidiol (CBD), a constituent of the Cannabis sativa, have accel... more RATIONALE The medical uses of cannabidiol (CBD), a constituent of the Cannabis sativa, have accelerated the legal and social acceptance for CBD-based medications but has also given the momentum for questioning whether the long-term use of CBD during the early years of life may induce adverse neurobiological effects in adulthood, including sleep disturbances. Given the critical window for neuroplasticity and neuro-functional changes that occur during stages of adolescence, we hypothesized that CBD might influence the sleep-wake cycle in adult rats after their exposure to CBD during the adolescence. OBJECTIVES Here, we investigated the effects upon behavior and neural activity in adulthood after long-term administrations of CBD in juvenile rats. METHODS We pre-treated juvenile rats with CBD (5 or 30 mg/Kg, daily) from post-natal day (PND) 30 and during 2 weeks. Following the treatments, the sleep-wake cycle and NeuN expression was analyzed at PND 80. RESULTS We found that systemic injections of CBD (5 or 30 mg/Kg, i.p.) given to adolescent rats (post-natal day 30) for 14 days increased in adulthood the wakefulness and decreased rapid eye movement sleep during the lights-on period whereas across the lights-off period, wakefulness was diminished and slow wave sleep was enhanced. In addition, we found that adult animals that received CBD during the adolescence displayed disruptions in sleep rebound period after total sleep deprivation. Finally, we determined how the chronic administrations of CBD during the adolescence affected in the adulthood the NeuN expression in the suprachiasmatic nucleus, a sleep-related brain region. CONCLUSIONS Our findings are relevant for interpreting results of adult rats that were chronically exposed to CBD during the adolescence and provide new insights into how CBD may impact the sleep-wake cycle and neuronal activity during developmental stages.
5-HT2A Receptors in the Central Nervous System, 2018
Several agents have been shown to improve sleep induction and/or maintenance in patients with pri... more Several agents have been shown to improve sleep induction and/or maintenance in patients with primary or comorbid insomnia. These include benzodiazepine and non-benzodiazepine receptor allosteric modulators, melatonin and the melatonin receptor agonist ramelteon, low dose doxepin, and suvorexant. However, benzodiazepines induce a further reduction of N3 sleep [slow wave sleep (SWS) or delta sleep] and rapid-eye-movement sleep (REMS), whereas values corresponding to these variables remain decreased during non-benzodiazepine, melatonin, ramelteon or low-dose doxepin administration. By contrast, suvorexant increases REMS. There is evidence indicating that non-selective (ritanserin, ketanserin, sertindole, ICI-170809, ICI-169369, RP-62203, SR-46349B) and selective (volinanserin, pruvanserin, eplivanserin) 5-HT2A receptor antagonists, as well as 5-HT2A receptor inverse agonists (nelotanserin, pimavanserin) increase SWS in laboratory animals and N3 sleep in subjects with normal sleep and/or patients with an insomnia disorder. Thus, the association of a selective 5-HT2A receptor antagonist or a 5-HT2A receptor inverse agonist with a hypnotic drug could be a valid alternative to normalize N3 sleep in patients with an insomnia complaint.
Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized in the... more Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized in the postero-lateral hypothalamus and incerto-hypothalamic area. These neurons project diffusely throughout the central nervous system and have been implicated in critical physiological processes, such as sleep. Unlike rodents, in the order carnivora as well as in humans, MCH exerts its biological functions through two receptors: MCHR-1 and MCHR-2. Hence, the cat is an optimal animal to model MCHergic functions in humans. In the present study, we examined the distribution of MCH-positive fibers in the brainstem of the cat. MCHergic axons with distinctive varicosities and boutons were heterogeneously distributed, exhibiting different densities in distinct regions of the brainstem. High density of MCHergic fibers was found in the dorsal raphe nucleus, the laterodorsal tegmental nucleus, the periaqueductal gray, the pendunculopontine tegmental nucleus, the locus coeruleus and the prepositus hyp...
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