Clinical Management of Sleep and Sleep Disorders With Cannabis and Cannabinoids: Implications to Practicing Psychiatrists.

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.

Microinjection of melanin-concentrating hormone (MCH) into the median raphe nucleus promotes REM sleep in rats.

Melanin concentrating hormone (MCH) is a sleep-promoting neuromodulator synthesized by neurons located in the postero-lateral hypothalamus and incerto-hypothalamic area. MCHergic neurons have widespread projections including the serotonergic dorsal (DR) and median (MnR) raphe nuclei, both involved in the control of wakefulness and sleep. In the present study, we explored in rats the presence of the MCH receptor type 1 (MCHR-1) in serotonergic neurons of the MnR by double immunofluorescence.

Clarifying the role of sleep in depression: A narrative review.

It has been established that 4.4 to 20% of the general population suffers from a major depressive disorder (MDD), which is frequently associated with a dysregulation of normal sleep-wake mechanisms. Disturbances of circadian rhythms are a cardinal feature of psychiatric dysfunctions, including MDD, which tends to indicate that biological clocks may play a role in their pathophysiology.

Hypocretin (orexin) immunoreactivity in the feline midbrain: Relevance for the generation of wakefulness.

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.

EEG dissociation induced by muscarinic receptor antagonists: Coherent 40 Hz oscillations in a background of slow waves and spindles.

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.

Pharmacotherapy of Insomnia.

Insomnia remains a common clinical concern that is associated with negative daytime consequences for patients and represents a significant public health problem for our society. Although a variety of therapies may be employed to treat insomnia, the use of medications has been a dominant approach. Regulatory agencies have now classified insomnia medications into 4 distinct pharmacodynamics classes.

The effects of local microinjection of selective dopamine D1 and D2 receptor agonists and antagonists into the dorsal raphe nucleus on sleep and wakefulness in the rat.

The effects of the dopamine (DA) D1 and D2 receptor agonists SKF38393, bromocriptine and quinpirole, respectively, on spontaneous sleep were analyzed in adult rats prepared for chronic sleep recordings. Local administration of the DAergic agonists into the dorsal raphe nucleus (DRN) during the light phase of the light-dark cycle induced a significant reduction of rapid-eye movement sleep (REMS) and the number of REM periods. Additionally, bromocriptine and quinpirole significantly increased wakefulness (W).

Microinjection of the dopamine D2-receptor antagonist Raclopride into the medial preoptic area reduces REM sleep in lactating rats.

The medial preoptic area (mPOA) is a brain structure classically related to both non-REM (NREM) sleep and maternal behavior. Although the dopaminergic system is known to play a role in the control of the states of sleep and wakefulness, its effects within the mPOA on sleep are still not clear. Microinjection of the dopamine D2 receptor antagonist Raclopride into the mPOA has been shown to promote nursing postures in lactating dams with no effects on active maternal behavior.

Zolpidem's use for insomnia.

Zolpidem is a short-acting non-benzodiazepine hypnotic drug that belongs to the imidazopyridine class. In addition to immediate-release (IR) and extended-release (ER) formulations, the new delivery forms including two sublingual tablets [standard dose (SD) and low dose (LD)], and an oral spray form have been recently developed which bypass the gastrointestinal tract. So far, Zolpidem has been studied in several clinical populations: cases poor sleepers, transient insomnia, elderly and non-elderly patients with chronic primary insomnia, and in comorbid insomnia.

Microinjection of the melanin-concentrating hormone into the sublaterodorsal tegmental nucleus inhibits REM sleep in the rat.

A study was performed on the effects of local microinjection of melanin-concentrating hormone (MCH) into the right sublaterodorsal tegmental nucleus (SLD) on sleep and wakefulness in rats prepared for chronic sleep recordings. MCH 200ng significantly decreased rapid-eye-movement sleep (REMS) time during the first and second 2-h of the recording period which was related to the reduction of the number of REMS periods and the increase of REMS latency. It is proposed that REMS inhibition was related to the direct deactivation of SLD glutamatergic neurons by the peptide.

The effects of second generation antipsychotic drugs on sleep variables in healthy subjects and patients with schizophrenia.

Insomnia is a common feature in schizophrenia, and is characterized by an increase of sleep latency (SL), as well as reductions in total sleep time (TST) and sleep efficiency (SE). Regarding sleep architecture, non-rapid-eye-movement (NREM) sleep, slow wave sleep (SWS) and rapid-eye-movement (REM) sleep latency are decreased, whereas REM sleep tends to remain unchanged. According to polysomnographic studies, clozapine, olanzapine, quetiapine and ziprasidone administration increased TST and/or SE in healthy subjects.

Melanin-Concentrating Hormone (MCH): Role in REM Sleep and Depression.

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.

The effects of systemic administration and local microinjection into the central nervous system of the selective serotonin 5-HT2C receptor agonist RO-600175 on sleep and wakefulness in the rat.

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.

When insomnia is not just insomnia: the deeper correlates of disturbed sleep with reference to DSM-5.

Recent scientific evidences have brought a paradigm shift in our approach towards the concepts of insomnia and its management. The differentiation between primary and secondary insomnia was proved more hypothetical than actual and based upon the current evidences insomnia subtypes described in earlier system have been lumped into one-insomnia disorder. Research in this field suggests that insomnia occurring during psychiatric or medical disorders has a bidirectional and interactive relationship with and coexisting medical and psychiatric illnesses.

Increased REM sleep after intra-locus coeruleus nucleus microinjection of melanin-concentrating hormone (MCH) in the rat.

A study was carried out on the effects of unilateral microinjection of melanin-concentrating hormone (MCH) into the right locus coeruleus (LC) on the sleep-wake cycle in rats prepared for chronic sleep recordings. MCH 200 ng significantly augmented rapid-eye-movement sleep (REMS) time during the first, second and third 2-h of recording. Furthermore, MCH 100 ng induced a significant increase of REMS during the first 2-h period after treatment.

The role of serotonin 5-HT7 receptor in regulating sleep and wakefulness.

Different approaches have been followed to characterize the role of 5-hydroxytryptamine (serotonin) receptor 7 (5-HT7) in the regulation of sleep-wake behavior: (1) 5-HT7 receptor knockout mice spend less time in rapid eye movement sleep than their wild-type counterparts, mainly during the light period. In contrast, there is no difference between the genotypes in time spent in wakefulness or slow-wave sleep. (2) Systemic administration of the selective 5-HT7 receptor agonist LP-211 significantly increased wakefulness (time spent awake) and reduced rapid eye movement sleep in the rat.

Systemic administration and local microinjection into the central nervous system of the 5-HT(7) receptor agonist LP-211 modify the sleep-wake cycle in the rat.

The effects of LP-211, a selective serotonin 5-HT7 receptor agonist were studied in adult rats implanted for chronic sleep recordings. Intraperitoneal administration of LP-211 (2.5-10mg/kg) during the light phase of the light-dark cycle significantly increased wakefulness (W) and reduced rapid-eye-movement sleep (REMS) and the number of REM periods during the 6-h recording period.

The effects of systemic and local microinjection into the central nervous system of the selective serotonin 5-HT6 receptor agonist WAY-208466 on sleep and wakefulness in the rat.

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.

Melanin-concentrating hormone control of sleep-wake behavior.

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.

Sleep and circadian rhythm dysregulation in schizophrenia.

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.

Microinjection of melanin concentrating hormone into the lateral preoptic area promotes non-REM sleep in the rat.

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.

Microinjection of the 5-HT7 receptor antagonist SB-269970 into the rat brainstem and basal forebrain: site-dependent effects on REM sleep.

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).