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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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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.

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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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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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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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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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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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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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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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