ArticleLiterature Review

The Emerging Role of the Endocannabinoid System in the Sleep-Wake Cycle Modulation

Authors:
  • Universidad Anáhuac Mayab. Mérida, Yucatán. México
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Abstract

The endocannabinoid system comprises amides, esters and ethers of long chain polyunsaturated fatty acids. Narachidonoylethanolamide (anandamide; ANA) and 2-arachidonoylglycerol (2-AG) are endogenous cannabinoids (endocannabinoids) ligands for the cannabinoid family of G-protein-coupled receptors named CB1 and CB2. Endocannabinoids are released upon demand from lipid precursors in a receptor-dependent manner and behave as retrograde signaling messengers, as well as modulators of postsynaptic transmission, interacting with other neurotransmitters systems. The two principal enzymes that are responsible for the metabolism of ANA and 2-AG are fatty acid amide hydrolase and monoacylglycerol lipase, respectively. Pharmacological experiments have shown that the administration of endocannabinoids induce cannabimimetic effects, including sleep promotion. This review will focus on some of the current evidence of the pharmacological potential of the endocannabinoid system on sleep modulation.

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... Given its ubiquitous expression in multiple brain areas, CB1 receptors modulate a variety of functions including learning and memory, mood, stress, anxiety, locomotion, social behaviors, arousal state, food intake, pain and sensory perception (Chaouloff et al., 2011;Corcoran et al., 2015;Lutz et al., 2015;Marsicano and Lafenêtre, 2009;Morena and Campolongo, 2014;Murillo-Rodriguez et al., 2011;Soria-Gómez et al., 2014a;Wei et al., 2017). In contrast, CB2 receptors are primarily found in the immune system at the periphery (Munro et al., 1993). ...
... neuropeptides, nitric oxide and endocannabinoids) in this brain region remains poorly investigated. One of the most important neuromodulatory systems in the brain is the ECS (Chaouloff et al., 2011;Corcoran et al., 2015;Lutz et al., 2015;Morena and Campolongo, 2014;Murillo-Rodriguez et al., 2011;Soria-Gómez et al., 2014a;Wei et al., 2017). However, the only few studies investigating the contribution of CB1 receptors in the PC were performed in the posterior part (pPC) and the available evidence does not allow determining the exact impact of the ECS in anterior par of PC (aPC) circuits and in related olfactory-guided behaviors (Ghosh et al., 2018;Zenko et al., 2011). ...
... In neurons, activation of pre-synaptic CB1 receptors results in the decrease of neurotransmitter release, inducing several forms of ECS-dependent synaptic plasticity (Araque et al. 2017;Busquets-Garcia, Bains, and Marsicano 2018;Castillo et al. 2012;Kano et al. 2009;Zou and Kumar 2018). Moreover, given the wide expression of CB1 receptors in multiple brain areas, the ECS modulates a large variety of cognitive processes, including learning and memory, anxiety, locomotion, food intake, sensory perception and many others (Chaouloff et al., 2011;Corcoran et al., 2015;Lutz et al., 2015;Morena and Campolongo, 2014;Murillo-Rodriguez et al., 2011;Soria-Gómez et al., 2014a;Wei et al., 2017). ...
Thesis
Impliquée dans de nombreuses fonctions comportementales, l'olfaction joue un rôle majeur quant à l'orientation de nos actions. Les odeurs communiquent avec le système nerveux central par l'intermédiaire de récepteurs situés dans l'épithélium olfactif du nez qui génèrent des signaux neuronaux, transmis et traités dans de nombreuses régions du cerveau. En particulier, le cortex piriforme antérieur (CPa) est une région olfactive importante impliquée dans la perception et l'intégration des odeurs. Étant donné le rôle du principal récepteur aux cannabinoïdes de type 1 (CB1) dans les fonctions sensorielles et les processus de mémoire, nous avons émis l'hypothèse que ces récepteurs pourraient moduler le traitement des odeurs dans le CPa. Pour ce faire, en combinant des approches anatomiques, électrophysiologiques et pharmacologiques, nous avons d'abord caractérisé la répartition des récepteurs CB1 et évalué leur capacité à réguler les circuits du CPa. Nous avons observé que ces récepteurs sont principalement exprimés dans les interneurones GABAergiques et que leur activation régule la transmission et la plasticité inhibitrice. Puis, nous avons cherché à déterminer le rôle et l'impact des récepteurs CB1 dans le traitement des odeurs dans le CPa. Grâce à une technique d'imagerie calcique in vivo, nous avons montré que l'altération de la signalisation des récepteurs CB1 affecte l'activité des neurones du CPa en réponse aux odeurs. En agissant très semblablement sur les circuits inhibiteurs locaux, nous avons mis en évidence que le fonctionnement physiologique des récepteurs CB1 dans le CPa est nécessaire pour le rappel d’une information olfactive apprise dans un contexte appétitif mais pas aversif. De façon générale, ces travaux permettent de mieux comprendre comment les récepteurs CB1 modulent les processus olfactifs dans le CPa.
... The endogenous cannabinoid (endocannabinoid) system regulates numerous circadian processes including food intake, peripheral metabolism, and body temperature via the suprachiasmatic nucleus (Vaughn et al. 2010;Ho et al. 2008;Prospero-Garcia et al. 2016;Murillo-Rodriguez et al. 2011) and is involved in the sleep/wake cycle, (Kesner and Lovinger 2020;Murillo-Rodriguez et al. 2011). The endocannabinoid system consists of lipid mediators that act upon specific receptors, including the nervous system (Kesner and Lovinger 2020;Prospero-Garcia et al. 2016;Murillo-Rodriguez et al. 2011). ...
... The endogenous cannabinoid (endocannabinoid) system regulates numerous circadian processes including food intake, peripheral metabolism, and body temperature via the suprachiasmatic nucleus (Vaughn et al. 2010;Ho et al. 2008;Prospero-Garcia et al. 2016;Murillo-Rodriguez et al. 2011) and is involved in the sleep/wake cycle, (Kesner and Lovinger 2020;Murillo-Rodriguez et al. 2011). The endocannabinoid system consists of lipid mediators that act upon specific receptors, including the nervous system (Kesner and Lovinger 2020;Prospero-Garcia et al. 2016;Murillo-Rodriguez et al. 2011). ...
... The endogenous cannabinoid (endocannabinoid) system regulates numerous circadian processes including food intake, peripheral metabolism, and body temperature via the suprachiasmatic nucleus (Vaughn et al. 2010;Ho et al. 2008;Prospero-Garcia et al. 2016;Murillo-Rodriguez et al. 2011) and is involved in the sleep/wake cycle, (Kesner and Lovinger 2020;Murillo-Rodriguez et al. 2011). The endocannabinoid system consists of lipid mediators that act upon specific receptors, including the nervous system (Kesner and Lovinger 2020;Prospero-Garcia et al. 2016;Murillo-Rodriguez et al. 2011). It can also influence temperature regulation, fat storage, mood and behaviour regulation, sensory perception, motor activity, nervous system modulation, and endocrine and gastrointestinal (GI) function (Vaughn et al., 2010) -all previously shown to have an effect on sleep (Vaughn et al., 2010). ...
Article
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Background Sleep is essential for wellbeing, yet sleep disturbance is a common problem linked to a wide range of health conditions. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide proposed to promote better sleep via potential interaction with the endocannabinoid system. Methods This double-blind, randomised study on 103 adults compared the efficacy and tolerability of 8 weeks of daily supplemented PEA formulation (350 mg Levagen + ®) to a placebo. Sleep quality and quantity were measured using wrist actigraphy, a sleep diary and questionnaires. Results At week 8, PEA supplementation reduced sleep onset latency, time to feel completely awake and improved cognition on waking. After 8 weeks, both groups improved their sleep quality and quantity scores similarly. There was no difference between groups at baseline or week 8 for sleep quantity or quality as measured from actigraphy or sleep diaries. Conclusion These findings support PEA as a potential sleeping aid capable of reducing sleep onset time and improving cognition on waking. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12618001339246. Registered 9th August 2018.
... For instance, the eCB system is thought to play an active role in regulatory processes, such as pain perception, memory, and sleep modulation [25,26]. Although the neurobiological basis of cannabis for sleep is still being understood, overlaps between the neuronal circuitry of sleep and wake states and the eCB system suggest that cannabinoids can contribute to sleep-related mechanisms and physiology [27][28][29]. Therefore, the eCB system has become a growing target in sleep research [25][26][27][28][29][30]. ...
... Although the neurobiological basis of cannabis for sleep is still being understood, overlaps between the neuronal circuitry of sleep and wake states and the eCB system suggest that cannabinoids can contribute to sleep-related mechanisms and physiology [27][28][29]. Therefore, the eCB system has become a growing target in sleep research [25][26][27][28][29][30]. Despite the perceived benefits of cannabinoids, there remains a lack of placebo-controlled trials that have examined the effects of the drug using validated sleep measures or objective sleep outcomes [11][12][13]. ...
Preprint
BACKGROUND Insomnia is a prevalent condition that presents itself at both the symptom and diagnostic levels. Although insomnia is one of the main reasons individuals seek medicinal cannabis, little is known about the profile of cannabinoid use or the perceived benefit of the use of cannabinoids in daily life. OBJECTIVE We conducted a retrospective study of medicinal cannabis users to investigate the use profile and perceived efficacy of cannabinoids for the management of insomnia. METHODS Data were collected using the Strainprint app, which allows medicinal cannabis users to log conditions and symptoms, track cannabis use, and monitor symptom severity pre- and postcannabis use. Our analyses examined 991 medicinal cannabis users with insomnia across 24,189 tracked cannabis use sessions. Sessions were analyzed, and both descriptive statistics and linear mixed-effects modeling were completed to examine use patterns and perceived efficacy. RESULTS Overall, cannabinoids were perceived to be efficacious across all genders and ages, and no significant differences were found among product forms, ingestion methods, or gender groups. Although all strain categories were perceived as efficacious, predominant indica strains were found to reduce insomnia symptomology more than cannabidiol (CBD) strains (estimated mean difference 0.59, SE 0.11; 95% CI 0.36-0.81; adjusted P <.001) and predominant sativa strains (estimated mean difference 0.74, SE 0.16; 95% CI 0.43-1.06; adjusted P <.001). Indica hybrid strains also presented a greater reduction in insomnia symptomology than CBD strains (mean difference 0.52, SE 0.12; 95% CI 0.29-0.74; adjusted P <.001) and predominant sativa strains (mean difference 0.67, SE 0.16; 95% CI 0.34-1.00; adjusted P =.002). CONCLUSIONS Medicinal cannabis users perceive a significant improvement in insomnia with cannabinoid use, and this study suggests a possible advantage with the use of predominant indica strains compared with predominant sativa strains and exclusively CBD in this population. This study emphasizes the need for randomized placebo-controlled trials assessing the efficacy and safety profile of cannabinoids for the treatment of insomnia.
... For instance, the eCB system is thought to play an active role in regulatory processes, such as pain perception, memory, and sleep modulation [25,26]. Although the neurobiological basis of cannabis for sleep is still being understood, overlaps between the neuronal circuitry of sleep and wake states and the eCB system suggest that cannabinoids can contribute to sleep-related mechanisms and physiology [27][28][29]. Therefore, the eCB system has become a growing target in sleep research [25][26][27][28][29][30]. ...
... Although the neurobiological basis of cannabis for sleep is still being understood, overlaps between the neuronal circuitry of sleep and wake states and the eCB system suggest that cannabinoids can contribute to sleep-related mechanisms and physiology [27][28][29]. Therefore, the eCB system has become a growing target in sleep research [25][26][27][28][29][30]. Despite the perceived benefits of cannabinoids, there remains a lack of placebo-controlled trials that have examined the effects of the drug using validated sleep measures or objective sleep outcomes [11][12][13]. ...
Article
Background Insomnia is a prevalent condition that presents itself at both the symptom and diagnostic levels. Although insomnia is one of the main reasons individuals seek medicinal cannabis, little is known about the profile of cannabinoid use or the perceived benefit of the use of cannabinoids in daily life. Objective We conducted a retrospective study of medicinal cannabis users to investigate the use profile and perceived efficacy of cannabinoids for the management of insomnia. Methods Data were collected using the Strainprint app, which allows medicinal cannabis users to log conditions and symptoms, track cannabis use, and monitor symptom severity pre- and postcannabis use. Our analyses examined 991 medicinal cannabis users with insomnia across 24,189 tracked cannabis use sessions. Sessions were analyzed, and both descriptive statistics and linear mixed-effects modeling were completed to examine use patterns and perceived efficacy. Results Overall, cannabinoids were perceived to be efficacious across all genders and ages, and no significant differences were found among product forms, ingestion methods, or gender groups. Although all strain categories were perceived as efficacious, predominant indica strains were found to reduce insomnia symptomology more than cannabidiol (CBD) strains (estimated mean difference 0.59, SE 0.11; 95% CI 0.36-0.81; adjusted P<.001) and predominant sativa strains (estimated mean difference 0.74, SE 0.16; 95% CI 0.43-1.06; adjusted P<.001). Indica hybrid strains also presented a greater reduction in insomnia symptomology than CBD strains (mean difference 0.52, SE 0.12; 95% CI 0.29-0.74; adjusted P<.001) and predominant sativa strains (mean difference 0.67, SE 0.16; 95% CI 0.34-1.00; adjusted P=.002). Conclusions Medicinal cannabis users perceive a significant improvement in insomnia with cannabinoid use, and this study suggests a possible advantage with the use of predominant indica strains compared with predominant sativa strains and exclusively CBD in this population. This study emphasizes the need for randomized placebo-controlled trials assessing the efficacy and safety profile of cannabinoids for the treatment of insomnia.
... Moreover, the blockade of the CB 1 cannabinoid receptor by pharmacological means facilitates alertness. Lastly, current evidence suggests the link between the endocannabinoid system and sleep disturbances, including narcolepsy [12][13][14][15][49][50][51][52][53][54][55][56]. ...
... The endocannabinoid system is integrated by the CB 1 /CB 2 cannabinoid receptors, the endogenous ligands AEA and 2-AG, and their respective metabolizing and synthetizing enzymes, as well as membrane transporter [1,2]. This neurobiological system has been described in multiple human biological samples, including the brain [1,2,[6][7][8][9][10][11], suggesting its role on the regulation of a broad neurobiological processes such as the sleep-wake cycle [12][13][14][15][49][50][51][52][53][54][55][56][57][58], which is also driven by a variety of neuroanatomical brain areas, neurochemicals, and circadian and homeostatic factors [16][17][18][19][20][21][22][23][24][25][26]. On the other hand, the sleep disorders are the pathological feature of sleep patterns described by the International Classification of Sleep Disorders [27], including insomnia and sleep-related breathing disorders, such as OSA. ...
Article
Full-text available
The endocannabinoid system is a neurobiological signaling network that is present in the human biological systems, including the brain. This neurobiological system comprises cannabinoid receptors, endogenous ligands, as well as enzymatic synthesis, degradation and transport of endocannabinoids and has been suggested as a modulator of multiple physiological processes, including the sleep–wake cycle. On the other hand, the COVID-19 pandemic, originated by the novel coronavirus SARS-CoV-2, has caused global catastrophes in economic, social, and health spheres. COVID-19 is a multi-organ disease with a broad spectrum of health complications, such as respiratory infections leading to respiratory-related symptoms and disorders. The development, approval, and application of vaccines against SARS-CoV-2 is ongoing; however, there are increasing reports of prolonged effects after COVID-19 infection, including respiratory and neurological sequelae. Here, I provide a comprehensive review of the current literature on the endocannabinoid system and their role in sleep modulation. Whilst I discuss relevant considerations for the high risk for developing sleep disorders related to respiratory failures, such as obstructive sleep apnea (OSA) in recovered COVID-19-infected subjects. Finally, I propose a framework that integrates the analysis of the components of the endocannabinoid system as prognostic biomarkers of the likely OSA after COVID-19 infection.
... Sleep is a complex behavior regulated by homeostatic and circadian factors that involve diverse brain circuits, endogenous molecules, and multiple neurotransmitter systems [42,43] as well as the endocannabinoid system, which includes endogenous ligands, receptors, enzymes and transporters [1,2,8,20]. Current evidence suggests that the endocannabinoid system modulates the sleep-wake cycle [25,36,38,[44][45][46][47][48]. While evidence regarding the role on sleep modulation of the endocannabinoid system elements, such as ANA [38,45,46], CB 1 cannabinoid receptor [46], or FAAH [40,48] have been suggested, further studies were needed to describe the effects of AMT inhibition on the sleep-wake cycle. ...
... Current evidence suggests that the endocannabinoid system modulates the sleep-wake cycle [25,36,38,[44][45][46][47][48]. While evidence regarding the role on sleep modulation of the endocannabinoid system elements, such as ANA [38,45,46], CB 1 cannabinoid receptor [46], or FAAH [40,48] have been suggested, further studies were needed to describe the effects of AMT inhibition on the sleep-wake cycle. Although a previous pharmacological report has shown that the AMT inhibitor VDM-11 promotes sleep and increases c-Fos expression in sleep-related brain areas such as the PVA [25], the pharmacological action of OMDM-2 on sleep remained unknown. ...
Article
The family of the endocannabinoid system comprises endogenous lipids (such as anandamide, [ANA]), receptors (CB(1)/CB(2) cannabinoid receptors), metabolic enzymes (fatty acid amide hydrolase [FAAH]) and the putative membrane transporter (anandamide membrane transporter [AMT]). Although the role of ANA, FAAH or the CB(1) cannabinoid receptor in sleep modulation has been reported, the effects of the inhibition of AMT on sleep remain unclear. In the present study, we show that microdialysis perfusion in rats of AMT inhibitors, (9Z)-N-[1-((R)-4-hydroxbenzyl)-2-hydroxyethyl]-9-octadecenamide (OMDM-2) or N-​(4-​hydroxy-​2-​methylphenyl)-​5Z,​8Z,​11Z,​14Z-​eicosatetraenamide (VDM-11; 10, 20 or 30μM; each compound) delivered into the paraventricular thalamic nucleus (PVA) increased sleep and decreased waking. In addition, the infusion of compounds reduced the extracellular levels of dopamine collected from nucleus accumbens. Taken together, these findings illustrate a critical role of AMT in sleep modulation.
... In addition, it was found that CBD enhanced the extracellular levels of dopamine collected from nucleus accumbens, whereas an increase in c-Fos expression was detected in waking-related brain areas, such as hypothalamus and dorsal raphe nucleus (Murillo-Rodríguez et al. 2006a, b). Similar findings were observed when CBD was injected into the lateral hypothalamus of rats during the lights-on period (Murillo-Rodríguez et al. 2008, 2011a. Recently, Hsiao et al. (2012) reported that CBD blocked anxiety-induced REMS suppression. ...
... The sleep-wake cycle is controlled by multiple neurochemical substrates, including exogenous and endogenous cannabinoids (Buonamici et al. 1982;Carlini and Cunha 1981;Feinberg et al. 1975Feinberg et al. , 1976Freemon 1972;Monti 1977;Murillo-Rodríguez et al. 2006a, b, 2008, 2011aNicholson et al. 2004;Pivik et al. 1972). In this chapter, we revised that phytocannabinoids modulate the sleep-wake cycle. ...
Chapter
Marijuana is a colloquial name given to Cannabis sativa, which has been used for diverse purposes, including as a therapeutical element for multiple health issues. The neurobiological effects of C. sativa involve a complex biological machinery including receptors, named CB1 and CB2 cannabinoid receptors. These receptors recognize endogenous cannabinoid-like compounds, such as anandamide and 2-arachinonolglycerol which seems to display sleep-inducing properties. Along decades, the study of the putative role of exogenous and endogenous cannabinoids in sleep modulation has brought critical data. Since endocannabinoids have been described in sleep-related brain areas, intriguing issues regarding whether hypothalamic substrates, such as MHC, may be interacting with the endocannabinoids have been raised.
... Recent evidence suggests that genetics may play a role in the etiology of the relationship between early cannabis use and adult sleep problems [18], and that there could be a common genetic liability for cannabis use and sleep problems that explain their relationship. Several lines of evidence are consistent with this common genetic model: the presence of genes believed to be involved with circadian rhythm/sleep in genomewide associations studies of lifetime cannabis use [39][40][41], clock gene genetic variants that are associated with cannabis addiction [42], and the possible role of the endocannabinoid system in the circadian rhythm/sleep-wake cycle [43][44][45][46]. Further research is needed on the possible shared genetics between cannabis use and clinical sleep outcomes such as insomnia. ...
... A recent study using similar twin models found that shared genetics may play a role in the etiology of the relationship between early cannabis use and adult sleep duration [18], and there are various additional lines of evidence consistent with this common genetic liability theory. Endocannabinoids may play a large part in this relationship, as the endocannabinoid system may be involved in the circadian sleep-wake cycle [43][44][45][46]. Endocannabinoids influence sleep, and their levels vary with time of day [45]. ...
Article
Full-text available
Study Objectives Estimate the genetic and environmental influences on the relationship between onset of regular cannabis use and young adult insomnia. Methods In a population-based twin cohort of 1882 twins (56% female, mean age = 22.99, SD = 2.97) we explored the genetic/environmental etiology of the relationship between onset of regular cannabis use and insomnia-related outcomes via multivariate twin models. Results Controlling for sex, current depression symptoms, and prior diagnosis of an anxiety or depression disorder, adult twins who reported early onset for regular cannabis use (age 17 or younger) were more likely to have insomnia (β = 0.07, p = 0.024) and insomnia with short sleep on weekdays (β = 0.08, p = 0.003) as young adults. We found significant genetic contributions for the onset of regular cannabis use (a2 = 76%, p < 0.001), insomnia (a2 = 44%, p < 0.001), and insomnia with short sleep on weekdays (a2 = 37%, p < 0.001). We found significant genetic correlations between onset of regular use and both insomnia (rA = 0.20, p = 0.047) and insomnia with short sleep on weekdays (rA = 0.25, p = 0.008) but no significant environmental associations between these traits. Conclusions We found common genetic liabilities for early onset of regular cannabis use and insomnia, implying pleiotropic influences of genes on both traits.
... Both fatty acids play a role in serotonin regulation (39), and the serotonergic system has been shown to play a critical role in sleep initiation and sleep maintenance (40). While AA has also been hypothesized to be involved in sleep-wake modulation (41,42), our findings do not suggest a prominent role of AA (or LA) in sleep duration or difficulty falling sleeping. ...
Article
Background: n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters. Objectives: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium. Methods: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA + DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n = 18,791) was categorized as short (≤6 h), 7-8 h (reference), or long (≥9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis. Results: In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified. Conclusions: Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.
... However, cannabis and two of its major components, Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are associated with disrupted sleep using objective measures (3). THC exerts its effects on the brain and body by binding to CB1 and CB2 receptors in the endocannabinoid system, which modulates the sleep-wake cycle (4). CB1 receptor antagonists increase wakefulness and reduce rapid eye movement (REM) time in animal studies (5)(6)(7)(8). ...
Article
Background: Cannabis has been shown to affect sleep in humans. Findings from animal studies indicate that higher endocannabinoid levels promote sleep, suggesting that chronic use of cannabis, which downregulates endocannabinoid activity, may disrupt sleep. Objectives: This study sought to determine if past-year cannabis use and genes that regulate endocannabinoid signaling, FAAH rs324420 and CNR1 rs2180619, predicted sleep quality. As depression has been previously associated with both cannabis and sleep, the secondary aim was to determine if depressive symptoms moderated or mediated these relationships. Methods: Data were collected from 41 emerging adult (ages 18-25) cannabis users. Exclusion criteria included Axis I disorders (besides SUD) and medical and neurologic disorders. Relationships were tested using multiple regressions, controlling for demographic variables, past-year substance use, and length of cannabis abstinence. Results: Greater past-year cannabis use and FAAH C/C genotype were associated with poorer sleep quality. CNR1 genotype did not significantly predict sleep quality. Depressive symptoms moderated the relationship between cannabis use and sleep at a nonsignificant trend level, such that participants with the higher cannabis use and depressive symptoms reported the more impaired sleep. Depressive symptoms mediated the relationship between FAAH genotype and sleep quality. Conclusions: This study demonstrates a dose-dependent relationship between chronic cannabis use and reported sleep quality, independent of abstinence length. Furthermore, it provides novel evidence that depressive symptoms mediate the relationship between FAAH genotype and sleep quality in humans. These findings suggest potential targets to impact sleep disruptions in cannabis users.
... Con-sciousness has been studied in neuroscience from different experimental perspectives, including electrophysiological correlates and neuroanatomical attempts [76][77][78][79]. Based on the given theoretical definition of consciousness, it can be inferred that current experimental data have demonstrated that the manipulation of the endocannabinoid system modulates consciousness by regulating alertness, fear, anxiety, pain perception, learning and memory, and sleep [80][81][82][83][84][85][86]. However, confirmatory experiments are needed to describe whether the FAAH, MAGL or AMT play relevant roles in the level of consciousness. ...
Article
Background & objective: Cannabinoids are derivatives that are either compounds occurring naturally in the plant, Cannabis sativa or synthetic analogs of these molecules. The first and most widely investigated of the cannabinoids is Δ9-tetrahydrocannabinol (Δ9-THC), which is the main psychotropic constituent of cannabis and undergoes significant binding to cannabinoid receptors. These cannabinoid receptors are seven-transmembrane receptors that received their name from the fact that they respond to cannabinoid compounds, including Δ9-THC. The cannabinoid receptors have been described in rat, human and mouse brains and they have been named the CB1 and CB2 cannabinoid receptors. Later, an endogenous molecule that exerts pharmacological effects similar to those described by Δ9-THC and binds to the cannabinoid receptors was discovered. This molecule, named anandamide, was the first of five endogenous cannabinoid receptor agonists described to date in the mammalian brain and other tissues. Of these endogenous cannabinoids or endocannabinoids, the most thoroughly investigated to date have been anandamide and 2-arachidonoylglycerol (2-AG). Over the years, a significant number of articles have been published in the field of endogenous cannabinoids, suggesting a modulatory profile in multiple neurobiological roles of endocannabinoids. The general consensus accepts that the endogenous cannabinoid system includes natural ligands (such as anandamide and 2- AG), receptors (CB1 and CB2), and the main enzymes responsible for the hydrolysis of anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) as well as the anandamide membrane transporter (AMT). To date, diverse pieces of evidence have shown that the endocannabinoid system controls multiple functions such as feeding, pain, learning and memory and has been linked with various disturbances, such as Parkinson´s disease. Among the modulatory properties of the endocannabinoid system, current data indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness, whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity. Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams. Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. Conclusion: Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences.
... Moreover, OEA infusion into the lateral hypothalamus reduced c-Fos expression in the cells of this area , although, the kind of neurotransmitter these cells synthesize and release was not determined. Regarding PEA, it also increases wakefulness when administered into the lateral hypothalamus, and into the dorsal raphe nucleus of rats, at the expense of NREM and REM sleep (Murillo-Rodriguez et al., 2011). In animal models, eCBs, such as AEA and 2-AG, reduce wakefulness while increasing sleep Murillo-Rodrıíguez et al., 1998;Pérez-Morales et al., 2013). ...
... A megnövekedett CB1 receptor aktiváció csökkenti a stressz válasz mértékét, amely kannabinoid agonisták adagolásával és a lebontó enzim, a zsírsavamid hidroláz (FAAH) gátlásával is elérhető (Patel et al., 2004). A kannabinoid agonisták továbbá, a CB1 recptorok közvetítésével, alvást indukáló hatással rendelkeznek (Murillo-Rodriguez et al., 2011). Az anandamid intracerebroventriculáris adagolása patkányokban alvást indukáló hatással rendelkezett, így csökkentette az ébrenlét és növelte mind a NREM, mind a REMs mennyiségét (Murillo-Rodriguez et al., 1998). ...
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The recreational drug ecstasy is widely used among dance clubbers for its acute euphoric and entactogenic effects. Ecstasy exerts its acute effects by increasing the extracellular concentration of monoamines in the brain by reversing the functions of reuptake mechanisms. These elevations in extracellular monoamine concentrations result in wake promoting effects, body hyperthermia and reductions in local cerebral blood flow. However, on the long-run, ecstasy reduces serotonin concentration and density of serotonergic markers in several brain areas. Functional deficits, like sleep disturbances, anxiogenic- and aggressive behavioral responses and mood disorders also may occur. However, one of the most prominent adverse effects is related to the cognitive functions. Following ecstasy use attenuated retro- and prospective memory and defective higher order cognitive functions can be observed, especially in heavy users. Several studies indicated the involvement of the endocannabinoid system, the sleep regulating centers and the hypothalamic-pituitary-adrenal axis based on or parallel to serotonergic damage in these processes. Recent evidence, however, also showed that changes in one of the latter systems can influence the functions of each other. In this review we summarize the related literature, and propose a complex mechanism for the long-lasting cognitive deficits following heavy ecstasy use.
... Alguns desses traços, sobretudo déficits em interação social e na extinção de memórias aversivas, aparecem em camundongos knockout para o gene que codifica o receptor de canabinoide do tipo 1 (CB1) e em ratos nascidos de mães tratadas com valproato durante a gravidez -que são modelos animais para o estudo de autismo correlatos aos casos humanos de autismo decorrentes de mulheres tratadas com valproato durante a gravidez (Chakrabarti et al., 2006;Dubreucq et al., 2011;Haller et al., 2004;Markram et al., 2007;Markram et al., 2008;Marsicano et al., 2002). Estas informações são consistentes com um grande número de evidências correlacionando o receptor CB1 com comportamento emocional e social tanto em roedores trole da plasticidade neuronal, na interação social, da cognição, na percepção de dor e outras informações sensoriais, no controle da ansiedade, e na suscetibilidade a convulsões que são fatores caracteristicamente comprometidos em pacientes portadores da Síndrome do X frágil (Ashton e Moore, 2011;Busquets-Garcia et al., 2013;Crowe et al., 2014;Giuffrida e Piomelli, 2000;Hill e Gorzalka, 2009;Kerr et al., 2013;Lightbody e Reiss, 2009;Marco e Laviola, 2011;Marco e Viveros, 2009;Marsicano e Lafenetre, 2009;Morena e Campolongo, 2014;Murillo-Rodriguez et al., 2011;Parolaro et al., 2010;Penagarikano et al., 2007;Pfeiffer e Huber, 2009;Puente et al., 2011;Ridaura-Ruiz et al., 2009;Tsiouris e Brown, 2004). ...
... Alguns desses traços, sobretudo déficits em interação social e na extinção de memórias aversivas, aparecem em camundongos knockout para o gene que codifica o receptor de canabinoide do tipo 1 (CB1) e em ratos nascidos de mães tratadas com valproato durante a gravidez -que são modelos animais para o estudo de autismo correlatos aos casos humanos de autismo decorrentes de mulheres tratadas com valproato durante a gravidez (Chakrabarti et al., 2006;Dubreucq et al., 2011;Haller et al., 2004;Markram et al., 2007;Markram et al., 2008;Marsicano et al., 2002). Estas informações são consistentes com um grande número de evidências correlacionando o receptor CB1 com comportamento emocional e social tanto em roedores trole da plasticidade neuronal, na interação social, da cognição, na percepção de dor e outras informações sensoriais, no controle da ansiedade, e na suscetibilidade a convulsões que são fatores caracteristicamente comprometidos em pacientes portadores da Síndrome do X frágil (Ashton e Moore, 2011;Busquets-Garcia et al., 2013;Crowe et al., 2014;Giuffrida e Piomelli, 2000;Hill e Gorzalka, 2009;Kerr et al., 2013;Lightbody e Reiss, 2009;Marco e Laviola, 2011;Marco e Viveros, 2009;Marsicano e Lafenetre, 2009;Morena e Campolongo, 2014;Murillo-Rodriguez et al., 2011;Parolaro et al., 2010;Penagarikano et al., 2007;Pfeiffer e Huber, 2009;Puente et al., 2011;Ridaura-Ruiz et al., 2009;Tsiouris e Brown, 2004). ...
... Based on findings that CB1Rs can control release of ACh (Gifford & Ashby, 1996;Gessa et al., 1997;Acquas et al., 2000Acquas et al., , 2001Kathmann et al., 2001), a role for eCBs in generation of state has been previously proposed (Murillo-Rodriguez et al., 1998;Murillo-Rodriguez, 2008). While evidence of inhibition of ACh release has been presented, rises noted in the hippocampus and cortical regions via a CB1R-mediated mechanism (Acquas et al., 2000(Acquas et al., , 2001 have led to the suggestion that CB1R-mediated actions in the pons, stimulated by endogenous production of eCBs, could lead to activation of cholinergic LDT neurons, leading to brainstem rises in ACh and thereby, via activation of the caudal reticular formation, participate in generation of the sleep states (Murillo-Rodriguez et al., 2011). The presynaptically invoked CB1R-mediated decrease in inhibition seen in the present study could play a role in CB1Rmediated increases in release of ACh, along with glutamate, when LDT activity is high via a feed-forward mechanism. ...
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Marijuana, which acts within the endocannabinoid (eCB) system as an agonist of the cannabinoid type 1 receptor (CB1R), exhibits addictive properties and has powerful actions on the state of arousal of an organism. The laterodorsal tegmental nucleus (LDT), as a component of the reticular activating system, is involved in cortical activation and is important in the development of drug addiction-associated behaviours. Therefore, eCBs might exert behavioural effects by actions on the LDT; however, it is unknown whether eCBs have actions on neurons in this nucleus. Accordingly, whole-cell voltage- and current-clamp recordings were conducted from mouse brain slices, and responses of LDT neurons to the CB1R agonist WIN-2 were monitored. Our results showed that WIN-2 decreased the frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs). Ongoing activity of endogenous eCBs was confirmed as AM251, a potent CB1R antagonist, elicited sIPSCs. WIN-2 reduced the firing frequency of LDT neurons. In addition, our RT-PCR studies confirmed the presence of CB1R transcript in the LDT. Taken together, we conclude that CB1Rs are functionally active in the LDT, and their activation changes the firing frequency and synaptic activity of neurons in this nucleus. Therefore, endogenous eCB transmission could play a role in processes involving the LDT, such as cortical activation and motivated behaviours and, further, behavioural actions of marijuana are probably mediated, in part, via cellular actions within the LDT induced by this addictive and behavioural state-altering drug.
... On the other hand, a novel potential method in the treatment for compulsive eating disorders may be taken into consideration. Some noteworthy findings suggest that CB 1 activation could also induce sleep promotion (Santucci et al., 1996;Murillo-Rodriguez et al., 2011). It may suggest the existence of an alternative mode of the DORAs' hypnotic action in the brain. ...
Article
Insomnia is a serious medical and social problem, its prevalence in the general population ranges from 9 to 35% depending on the country and assessment method. Often, patients are subject to inappropriate and therefore dangerous pharmacotherapies that include prolonged administration of hypnotic drugs, benzodiazepines and other GABAA receptor modulators. This usually does not lead to a satisfactory improvement in patients' clinical states and may cause lifelong drug dependence. Brain state transitions require the coordinated activity of numerous neuronal pathways and brain structures. It is thought that orexin-expressing neurons play a crucial role in this process. Due to their interaction with the sleep-wake-regulating neuronal population, they can activate vigilance-promoting regions and prevent unwanted sleep intrusions. Understanding the multiple orexin modulatory effects is crucial in the context of pathogenesis of insomnia and should lead to the development of novel treatments. An important step in this process was the synthesis of dual antagonists of orexin receptors. Crucially, these drugs, as opposed to benzodiazepines, do not change the sleep architecture and have limited side-effects. This new pharmacological approach might be the most appropriate to treat insomnia.
... More recent studies have demonstrated that n-3 LC-PUFA derivatives of endocannabinoids also exist [63][64][65]. Endocannabinoid action via cannabinoid 1 and 2 receptors impacts a wide range of biological functions including energy balance and metabolism, mood, memory, sleep, reproduction, thermoregulation and immune function [63][64][65][66][67][68][69][70][71][72][73][74][75]. Endocannabinoids can also be metabolized by cyclooxygenases, lipoygenases, and p450 epoxygenases to form other biologically-active complex lipids [65,76,77]. ...
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Background: Dietary essential omega-6 (n-6) and omega-3 (n-3) 18 carbon (18C-) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), can be converted (utilizing desaturase and elongase enzymes encoded by FADS and ELOVL genes) to biologically-active long chain (LC; >20)-PUFAs by numerous cells and tissues. These n-6 and n-3 LC-PUFAs and their metabolites (ex, eicosanoids and endocannabinoids) play critical signaling and structural roles in almost all physiologic and pathophysiologic processes. Methods: This review summarizes: (1) the biosynthesis, metabolism and roles of LC-PUFAs; (2) the potential impact of rapidly altering the intake of dietary LA and ALA; (3) the genetics and evolution of LC-PUFA biosynthesis; (4) Gene-diet interactions that may lead to excess levels of n-6 LC-PUFAs and deficiencies of n-3 LC-PUFAs; and (5) opportunities for precision nutrition approaches to personalize n-3 LC-PUFA supplementation for individuals and populations. Conclusions: The rapid nature of transitions in 18C-PUFA exposure together with the genetic variation in the LC-PUFA biosynthetic pathway found in different populations make mal-adaptations a likely outcome of our current nutritional environment. Understanding this genetic variation in the context of 18C-PUFA dietary exposure should enable the development of individualized n-3 LC-PUFA supplementation regimens to prevent and manage human disease.
... Anandamide may act as a neurotransmitter promoting sleep by enhancing the levels of the sleep-inducing molecule adenosine. 56,57 Furthermore, CB2 receptor agonists may protect against cerebral ischemia and reperfusion injury by decreasing the inflammatory and immune response and promoting a vasodilatation effect. 58 Anandamide levels have been analyzed in plasma from groundhogs using LC−MS analysis, but no differences were seen between summer active and torpid animals. ...
Article
Syrian hamster undergoes a reversible hyperphosphorylation of protein tau during hibernation, providing a unique natural model that may unveil the physiological mechanisms behind this critical process involved in the development of Alzheimer’s disease and other tauopathies. The hibernation cycle of these animals fluctuates between two stages: 34 days of torpor bouts interspersed with periods of euthermia called arousals that last several hours. In this study, we investigated for the first time the metabolic changes in brain tissue during hibernation. A total of 337 metabolites showed statistically significant differences during hibernation. Based on these metabolites, several pathways were found to be significantly regulated and, therefore, play a key role in the regulation of hibernation processes. The increase in the levels of ceramides containing more than 20 C atoms was found in torpor animals, reflecting a higher activity of CerS2 during hibernation, linked to neurofibrillary tangle generation and structural changes in the Golgi apparatus. Our results open up the debate about the possible significance of some metabolites during hibernation, which may possibly be related to tau phosphorylation and dephosphorylation events. In general, this study may provide insights into novel neuroprotective agents since the alterations described throughout the hibernation process are reversible.
... Recently, the field of the endocannabinoids has grown in popularity since the discovery of endogenous cannabinoid receptors in the brain (Matsuda et al., 1990) and their most relevant endocannabinoids ligands. Multiple studies have reported its role on a variety of brain structures and cognitive functions like memory, appetite, metabolism, immune system, mood and sleep (Murillo-Rodriguez et al., 2011;Tanasescu and Constantinescu, 2010;Zanettini et al., 2011). ...
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Major depressive disorder is a high-impact, debilitating disease and it is currently considered the most prevalent mental illness. It is associated with disability, as well as increased morbidity and mortality. Despite its significant repercussions in our society, its exact pathophysiology remains unclear and therefore, available antidepressant treatment options are limited and, in some cases, ineffective. In the past years, research has focused on the development of a multifactorial theory of depression. Simultaneously, evidence supporting the role of the endocannabinoid system in the neurobiology of neuropsychiatric diseases has emerged. Studies have shown that the endocannabinoid system strongly impacts neurotransmission, and the neuroendocrine and neuroimmune systems, which are known to be dysfunctional in depressive patients. Accordingly, common antidepressants were shown to have a direct impact on the expression of cannabinoid receptors throughout the brain. Therefore, the relationship between the endocannabinoid system and major depressive disorder is worth consideration. Nevertheless, most studies focus on smaller pieces of what is undoubtedly a larger mosaic of interdependent processes. Therefore, the present review summarizes the existing literature regarding the role of the endocannabinoid system in depression aiming to integrate this information into a holistic picture for a better understanding of the relationship between the two.
... Intracerebroventricular administration of the eCB anandamide (ANA) during the lights-on period caused diminution in wakefulness, while increased non-REMS and REMS in rats. This effect was more evident when ANA was injected directly into the PPT nucleus, and SR141716a prevented this effect [37,38]. Experimental evidence indicates that the activation of the CB 1 receptors promotes the release of acetylcholine (ACh) in cortical and hippocampal areas [39]. ...
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Background Previous data show that serotonin 2C (5-HT2C) and cannabinoid 1 (CB1) receptors have a role in the modulation of sleep–wake cycle. Namely, antagonists on these receptors promoted wakefulness and inhibited rapid eye movement sleep (REMS) in rodents. The interaction of these receptors are also present in other physiological functions, such as the regulation of appetite. Blockade of 5-HT2C receptors modulat the effect of CB1 receptor antagonist, presumably in consecutive or interdependent steps. Here we investigate, whether previous blockade of 5-HT2C receptors can affect CB1 receptor functions in the sleep–wake regulation. Results Wistar rats were equipped with electroencephalography (EEG) and electromyography (EMG) electrodes. Following the recovery and habituation after surgery, animals were injected intraperitoneally (ip.) with SB-242084, a 5-HT2C receptor antagonist (1.0 mg/kg) at light onset (beginning of passive phase) followed by an injection with AM-251, a CB1 receptor antagonist (5.0 or 10.0 mg/kg, ip.) 10 min later. EEG, EMG and motor activity were analyzed for the subsequent 2 h. Both SB-242084 and AM-251 increased the time spent in active wakefulness, while decreased the time spent in non-REMS and REMS stages in the first 2 h of passive phase. In combination, the effect of the agents were additive, furthermore, statistical analysis did not show any interaction between the effects of these drugs in the modulation of vigilance stages. Conclusions Our results suggest that 5-HT2C receptor blockade followed by blockade of CB1 receptors evoked additive effect on the regulation of sleep–wake pattern.
... For example, microinjections of CBD into a lateral ventricle (icv) or lateral hypothalamus produced significant increases in the extracellular DA in the NAc. 87,88 However, intra-NAc microinjection of CBD produced an inhibitory effect on VTA DA neuronal activity by itself 89 and attenuated amphetamine-induced locomotor sensitization and VTA DA neuronal sensitization. 89,90 Although the authors proposed that 5-HT 1A mechanisms may underlie intra-NAc CBD-induced reduction in NAc DA, 90,91 there is no direct evidence to support it. ...
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A growing number of studies suggest therapeutic applications of cannabidiol (CBD), a recently U.S. Food and Drug Administration (FDA)–approved medication for epilepsy, in treatment of many other neuropsychological disorders. However, pharmacological action and the mechanisms by which CBD exerts its effects are not fully understood. Here, we examined the effects of CBD on oral sucrose self‐administration in rodents and explored the receptor mechanisms underlying CBD‐induced behavioral effects using pharmacological and transgenic approaches. Systemic administration of CBD (10, 20, and 40 mg/kg, ip) produced a dose‐dependent reduction in sucrose self‐administration in rats and in wild‐type (WT) and CB1−/− mice but not in CB2−/− mice. CBD appeared to be more efficacious in CB1−/− mice than in WT mice. Similarly, pretreatment with AM251, a CB1R antagonist, potentiated, while AM630, a selective CB2R antagonist, blocked CBD‐induced reduction in sucrose self‐administration, suggesting the involvement of CB1 and CB2 receptors. Furthermore, systemic administration of JWH133, a selective CB2R agonist, also produced a dose‐dependent reduction in sucrose self‐administration in WT and CB1−/− mice, but not in CB2−/− mice. Pretreatment with AM251 enhanced, while AM630 blocked JWH133‐induced reduction in sucrose self‐administration in WT mice, suggesting that CBD inhibits sucrose self‐administration likely by CB1 receptor antagonism and CB2 receptor agonism. Taken together, the present findings suggest that CBD may have therapeutic potential in reducing binge eating and the development of obesity. Cannabidiol is a recently U.S. FDA approved medication for the treatment of epilepsy. In this study, we found that it is also effective in controlling food‐taking behavior in rats and mice largely by activation of cannabinoid CB2 receptor.
... In addition, the endocannabinoid system is integrated by several molecular elements, including the enzymes that synthesize/degrade anandamide (fatty acid hydrolase [FAAH]) or 2-AG (monoacylglycerol lipase [MAGL]), the anandamide membrane transporter (AMT) and the receptor channel TRPV1 (Transient Receptor Potential Vanilloid 1; [78][79][80][81][82]). Along the decades, preclinical studies have shown that the endocannabinoid system exerts critical neurobiological functions, some of them, with clinical relevance, including the control of the sleep-wake cycle [80,[83][84][85][86][87][88][89][90][91][92][93]]. ...
Article
Aging is an inevitable process that involves changes along life in multiple neurochemical, neuroanatomical, hormonal systems, and many others. In addition, these biological modifications lead to an increase in age-related sickness such as cardiovascular diseases, osteoporosis, neurodegenerative disorders, and sleep disturbances, among others that affect activities of daily life. Demographic projections have demonstrated that aging will increase its worldwide rate in the coming years. The research on chronic diseases of the elderly is important to gain insights into this growing global burden. Novel therapeutic approaches aimed for treatment of age-related pathologies have included the endocannabinoid system as an effective tools since this biological system shows beneficial effects in preclinical models. However, and despite these advances, little has been addressed in the arena of the endocannabinoid system as option for treating sleep disorders in aging since experimental evidence suggests that some elements of the endocannabinoid system modulate the sleep-wake cycle. This article addresses this less-studied field, focusing on the likely perspective of the implication of the endocannabinoid system in the regulation of sleep problems reported in aged. We conclude that beneficial effects regarding the putative efficacy of the endocannabinoid system as therapeutic tools in aging is either inconclusive or still missing.
... Nonetheless, some animal studies have pointed to a possible beneficial role of AA on sleep (38). The association also has biological plausibility, because AA is a precursor of anandamide, a cannabinoid that is involved in the initiation of sleep (39). ...
Article
Background: Delayed sleep timing and short sleep duration represent a significant public health burden in adolescents. Whether intake of nutrients affects the pineal gland, where sleep/wake cycles are regulated, remains unclear. Objectives: In a cross-sectional analysis, we investigated whether plasma concentrations of DHA and arachidonic acid (AA), long-chain fatty acids that can be obtained through diet, were related to sleep timing and duration in adolescents. Methods: The study population included 405 Mexico City adolescents (mean age ± SD = 14.2 ± 2.1 y; 48% males) who took part in a 2015-2016 follow-up visit as a part of an ongoing cohort study. Fatty acid concentrations were measured in plasma using GLC, as a percentage of total fatty acids. Sleep midpoint and duration were assessed with 7-d wrist actigraphy. We categorized DHA and AA plasma concentrations into quartiles (Q1-Q4; Q4 = highest fatty acids). We conducted cross-sectional linear regression analysis with sleep characteristics as separate outcomes and quartiles of DHA and AA as exposures, adjusting for sex, age, and BMI z-scores. Results: Mean ± SD plasma DHA (as percentage of total fatty acids) was 1.2 ± 0.4%, whereas mean ± SD plasma AA was 6.2 ± 1.5%. In adjusted analysis, higher plasma DHA was linearly associated with longer sleep duration on the weekends; to illustrate, those in Q4 compared with Q1 had 32 min longer duration (95% CI: 7, 57; P trend = 0.005). Higher DHA was also associated with earlier sleep timing during weekdays and weekends, although in a nonlinear fashion. The largest difference was a 0.75-h (45-min) later sleep midpoint in Q2 compared with Q4 (95% CI: 0.36, 1.14). Conclusions: Plasma DHA was associated with earlier sleep timing and longer weekend sleep duration in Mexican adolescents. Whether DHA supplementation improves sleep in adolescent populations deserves consideration in randomized trials.
... Along these lines, the EC system has been implicated in mediating some of the effects of the general anesthetic propofol (Patel et al., 2003), but there are currently no data available as to the effects of urethane on the EC system, making data from the in vivo studies difficult to interpret in light of conflicting results. Additionally, a nascent but growing body of evidence has linked the EC system to the regulation of the sleep/wake cycle (for review see Murillo- Rodriguez et al., 2011). As a consequence, future studies should be sensitive to the possible interactions between the EC system and the state of the organism under study. ...
Chapter
The endogenous cannabinoid system is an important regulatory system involved in physiological homeostasis. Endocannabinoid signaling is known to modulate neural development, immune function, metabolism, synaptic plasticity, and emotional state. Accumulating evidence also implicates brain endocannabinoid signaling in the processing of natural and drug-induced reward states and dysregulated endocannabinoid signaling in the etiology of aberrant reward function and drug addiction. In this chapter, we discuss the influence of endocannabinoid signaling on the rewarding and motivational effects of natural rewards such as food, sex, and social interaction, as well as evidence demonstrating an endocannabinoid influence in the rewarding effects of abused drugs. The effects of long-term drug consumption on endocannabinoid signaling are discussed, along with evidence that the resultant dysregulation of endocannabinoid function contributes to various aspects of drug dependence and addiction including physical symptoms of drug withdrawal, increased stress responsivity, negative affective states, dysregulated synaptic plasticity, dysregulated extinction of drug-related memories, relapse to drug taking, and impaired cognitive function. Lastly, consideration is given to the role for dysregulated endocannabinoid signaling in pathological food reward and eating disorders.
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Introduction: Insomnia in Major Depressive Disorder (MDD) is highly prevalent and associated with increased suffering and functional impairment. Effective, evidence-based treatments for insomnia in MDD are an unmet need in clinical practice. Areas covered: Herein, the authors provide a review of the clinical correlates, putative neurobiological mechanisms and treatment options for the management of insomnia in individuals with MDD. Expert opinion: Sleep disturbances in MDD should be recognized as at least one of the following: 1) a domain of depressive psychopathology; 2) a consequence of rhythm disruptions; 3) a manifestation of comorbidities of sleep disturbances; 4) a manifestation of the influence of sex hormones in the brain in MDD; 5) a general medical comorbidity; and 6) a side effect of antidepressant medications. Assessment of insomnia in clinical practices is routinely performed with the use of non- structured interviews. Other methods, such as standardized questionnaires and sleep diaries, along with complementary methods such as actigraphy, and polysomnography are more scarcely applied. Smartphones and personal devices offer a promising strategy with the use of passive, long-lasting, and ecologically valid assessments despite the lack of studies specifically targeting insomnia in individuals with MDD. New therapeutic approaches are essential, including novel targets such as orexins/hypocretin and the endocannabinoid system.
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In an increasing number of states and countries, cannabis now stands poised to join alcohol and tobacco as a legal drug. Quantifying the relative adverse and beneficial effects of cannabis and its constituent cannabinoids should therefore be prioritized. Whereas newspaper headlines have focused on links between cannabis and psychosis, less attention has been paid to the much more common problem of cannabis addiction. Certain cognitive changes have also been attributed to cannabis use, although their causality and longevity are fiercely debated. Identifying why some individuals are more vulnerable than others to the adverse effects of cannabis is now of paramount importance to public health. Here, we review the current state of knowledge about such vulnerability factors, the variations in types of cannabis, and the relationship between these and cognition and addiction.
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The brain reward system is critical for survival. The hedonic effects produced by eating, exercise and sexual activity provide important motivational effects that increase the likelihood of future engagement in these criti­ cal activities (that is, positive reinforcement). The reward system is also essential for important negative hedonic responses, in which aversive or unpleasant events (for example, sickness or bodily harm) increase the likeli­ hood of behaviours that will avoid or relieve these negative states (that is, negative reinforcement). Seminal discoveries demonstrating that the effects of marijuana (cannabis sativa) are mediated by canna­ binoid receptors in the brain propelled significant research initiatives that expanded our knowledge about the body's endogenous cannabinoid system (termed the endocannabinoid (eCB) system (ECS)), which is now acknowledged to have a prominent role in modulat­ ing brain reward function and maintaining emotional homeostasis. This Review examines the evidence for an eCB influence in the positive­reinforcing effects of natural rewards and drugs of abuse. In contrast to the initial pleasurable experience of rewarding stimuli, pro­ longed drug exposure contributes to aberrant synaptic plasticity, negative emotional states and impaired learn­ ing and memory processes that sustain compulsive drug consumption, which is characteristic of the addicted state. We explore the ECS signalling underlying these maladaptive processes and provide an overview of the existing literature regarding the genetic factors that are associated with the ECS to gain insight about the potential contribution of ECS signalling dysregulation to addiction disorders.
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Background: Limited evidence suggests that early cannabis use is associated with sleep problems. Research is needed to understand the developmental impact of early regular cannabis use on later adult sleep duration. Methods: In a sample of 1656 adult twins (56% female, Mean age = 25.79yrs), linear mixed effects models were used to analyze the influence of retrospectively assessed age of onset of regular cannabis use on adult sleep duration controlling for sex, depression, and current substance use. Twin analyses provided genetic and environmental variance estimates as well as insights into the association and potential casual relationships between these traits. Results: Earlier age of onset for regular cannabis use was significantly associated with shorter adult sleep duration on both weekdays (β = -0.13, 95% CI = [-0.23, -0.04]) and weekends (β = -0.18, 95% CI = [-0.27, -0.08]). Additive genetics significantly contributed to the onset of regular cannabis use (a2 = 76%, 95% CI = [68, 85]) and adult weekend sleep duration (a2 = 20%, 95% CI = [11, 32]). We found evidence of a significant genetic correlation (rA = -0.31, 95% CI = [-0.41, -0.15]) between these two traits and our best fitting model was consistent with early onset of regular cannabis use causing shorter adult weekend sleep duration (β = -0.11, 95% CI = [-0.18, -0.03]). Conclusions: Our results are consistent with the hypothesis that early onset of regular cannabis use may have a negative impact on adult sleep duration.
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Pain and sleep share a bidirectional relationship, with each influencing the other. Several excellent reviews have explored this relationship. In this article, we revisit the evidence and explore existing research on this complex inter-relationship. The primary focus of the article is on the pharmacological treatment of chronic non-malignant pain and the main purpose is to review the effect of various pharmacological agents used in the management of chronic pain on sleep. This has not been comprehensively done before. We explore the clinical use of these agents, their impact on sleep architecture and sleep physiology, the mechanism of action on sleep parameters and sleep disorders associated with these agents. Pharmacological classes reviewed include antidepressants, opioid analgesics, anti-epileptics, cannabinoids and non-steroidal anti-inflammatory agents, drugs most commonly used to manage chronic pain. The objective is to help health professionals gain better insight into the complex effect that commonly used analgesics have on an individual’s sleep and how this could impact on the effectiveness of the drug as an analgesic. We conclude that antidepressants have both positive and negative effects on sleep, so do opioids, but in the latter case the evidence shifts towards the counterproductive side. Some anticonvulsants are sleep sparing and non-steroidal anti-inflammatory drugs (NSAIDs) are sleep neutral. Cannabinoids remain an underexplored and researched group.
Article
Study objectives: Estimate the genetic relationship of cannabis use with sleep deficits and eveningness chronotype. Methods: We used linkage disequilibrium score regression (LDSC) to analyze genetic correlations between sleep deficits and cannabis use behaviors. Secondly, we generated sleep deficit polygenic risk scores (PRS) and estimated their ability to predict cannabis use behaviors using linear and logistic regression. Summary statistics came from existing genome wide association studies (GWAS) of European ancestry that were focused on sleep duration, insomnia, chronotype, lifetime cannabis use, and cannabis use disorder (CUD). A target sample for PRS prediction consisted of high-risk participants and participants from twin/family community-based studies (European ancestry; n = 760, male = 64%; mean age = 26.78 years). Target data consisted of self-reported sleep (sleep duration, feeling tired, and taking naps) and cannabis use behaviors (lifetime ever use, number of lifetime uses, past 180-day use, age of first use, and lifetime CUD symptoms). Results: Significant genetic correlation between lifetime cannabis use and eveningness chronotype (rG = 0.24, p < 0.001), as well as between CUD and both short sleep duration (<7 h) (rG = 0.23, p = 0.017) and insomnia (rG = 0.20, p = 0.020). Insomnia PRS predicted earlier age of first cannabis use (OR = 0.92, p = 0.036) and increased lifetime CUD symptom count (OR = 1.09, p = 0.012). Conclusion: Cannabis use is genetically associated with both sleep deficits and an eveningness chronotype, suggesting that there are genes that predispose individuals to both cannabis use and sleep deficits.
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Background: Sleep is essential for wellbeing, yet sleep disturbance is a common problem linked to a wide range of health conditions. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide proposed to promote better sleep via potential interaction with the endocannabinoid system. Methods: This double-blind, randomized study on 103 adults compared the efficacy and tolerability of 8 weeks of daily supplemented PEA formulation (350 mg Levagen+TM) to a placebo. Sleep quality and quantity were measured using wrist actigraphy, a sleep diary and questionnaires. Results: At week 8, PEA supplementation reduced sleep onset latency, time to feel completely awake and improved cognition on waking. After 8 weeks, both groups improved their sleep quality and quantity scores similarly. There was no difference between groups at baseline or week 8 for sleep quantity or quality as measured from actigraphy or sleep diaries. Conclusion: These findings support PEA as a potential sleeping aid capable of reducing sleep onset time and improving cognition on waking. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12618001339246. Registered 9th August 2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375493&isReview=true
Article
Introduction: There is widespread literature on the interaction between cannabis use and sleep, yet the mechanisms that underlie this relationship are not well understood. Several factors lead to inconsistencies in this relationship suggesting a nuanced interaction between cannabis and sleep. An important question that remains to be addressed is the temporal relationship between disrupted sleep and cannabis use. This literature review summarizes the existing literature on the association between disrupted sleep and cannabis toward the goal of addressing the question of the chronology of these reported effects. Materials and Methods: We conducted a review of the literature using PubMed to summarize current knowledge on the association between cannabis use and sleep in humans. Results: We identified 31 studies on the association of cannabis use and sleep. The findings from these studies were mixed. Cannabis was associated with a variety of impacts on sleep ranging from beneficial effects, such as reduced sleep-onset latency, to negative outcomes, such as reduced sleep duration and suppressed rapid eye movement oscillations. The chronology of the interaction of cannabis and sleep was unclear, although much of the current literature focus on factors that modulate how cannabis impairs sleep after initial use. Conclusion: There was sufficient evidence to suggest that cannabis use alters circadian rhythms, and hence, negatively impacts sleep. The current literature is largely from studies utilizing self-report measures of sleep; thus, objective measures of sleep are needed. In addition, although there were no empirical studies on the temporal relationship between cannabis use and sleep, the majority of the literature focused on characterizing sleep impairment after cannabis use.
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In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2--the two cannabinoid receptors identified thus far--with Ki values of 472 +/- 55 and 1400 +/- 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of delta 9-tetrahydrocannabinol (delta 9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of delta 9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than delta 9-THC.
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A molecule isolated from the cerebrospinal fluid of sleep-deprived cats has been chemically characterized and identified as cis-9,10-octadecenoamide. Other fatty acid primary amides in addition to cis-9,10-octadecenoamide were identified as natural constituents of the cerebrospinal fluid of cat, rat, and human, indicating that these compounds compose a distinct family of brain lipids. Synthetic cis-9,10-octadecenoamide induced physiological sleep when injected into rats. Together, these results suggest that fatty acid primary amides may represent a previously unrecognized class of biological signaling molecules.
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We report the isolation of a heretofore unrecognized brain lipid that is present in cerebrospinal fluid of sleep-deprived cats. The molecule appears to be a long-chain base structurally related to sphingosine and sphinganine in which a second unsaturated bond has been introduced. An increase in the degree of unsaturation of a key membrane component is expected to have important physiological consequences.
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Mesopontine cholinergic neurons have long been thought to play a key role in behavioral state control. In particular, they have been implicated in the process of EEG desynchrony and in the generation of rapid eye movement (REM) sleep. However, the behavioral profile of identified mesopontine cholinergic neurons has not been unequivocally demonstrated. In an attempt to address this issue, in vivo microdialysis was used to monitor acetylcholine (ACh) release across behavioral state in the rat thalamus, a major projection site of mesopontine cholinergic neurons. Because REM periods in rats are of short duration, a method was developed to collect and accumulate sufficiently large samples from each of the individual states of wake, slow-wave sleep, and REM sleep to permit off-line analysis via (HPLC-ECD). Probe placement and the source of cholinergic innervation to the vicinity of the microdialysis probe were verified using retrograde tracing combined with ChAT immunohistochemistry. Finally, the sodium and calcium dependence of ACh measured in the thalamus were tested using TTX and calcium-free dialysates. The results showed that (1) extracellular ACh concentrations in the thalamus are high during both wake and REM sleep and significantly lower during slow-wave sleep, (2) the majority of cholinergic projections to the vicinity of the dialysis probes originate in the mesopontine tegmentum, and (3) ACh release in the thalamus is due to sodium- and calcium-dependent mechanisms. In contrast to predictions of some previous hypotheses, these results demonstrate that mesopontine cholinergic neurons are active during both wake and REM sleep.
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ANANDAMIDE (N-arachidonoyl-ethanolamine) was recently identified as a brain arachidonate derivative that binds to and activates cannabinoid receptors1–4, yet the mechanisms underlying formation, release and inactivation of this putative messenger molecule are still unclear. Here we report that anandamide is produced in and released from cultured brain neurons in a calcium ion-dependent manner when the neurons are stimulated with membrane-depolarizing agents. Anandamide formation occurs through phos-phodiesterase-mediated cleavage of a novel phospholipid precursor, N-arachidonoyl-phosphatidylethanolamine. A similar mechanism also governs the formation of a family of anandamide congeners, whose possible roles in neuronal signalling remain unknown. Our results and those of others5,6indicate therefore that multiple biochemical pathways may participate in anandamide formation in brain tissue. The life span of extracellular anandamide is limited by a rapid and selective process of cellular uptake, which is accompanied by hydrolytic degradation to ethanolamine and arachidonate. Our results thus strongly support the proposed role of anandamide as an endogenous neuronal messenger.
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Anandamide (ANA) alters sleep by increasing the amount of time spent in slow wave sleep 2 (SWS2) and rapid eye movement sleep (REMS) at the expense of wakefulness (W) in rats. In this report, we describe a similar effect of ANA when injected itracerebroventricularly (i.c.v.) or into the peduriculopontine tegmental nucleus (PPTg) and the lack of an effect when ANA is administered into the medial preoptic area (MPOA). Furthermore, the i.c.v. or PPTg administration of SR141716A, a CB1 antagonist, or U73122, a PLC inhibitor, 15 min prior to ANA, readily prevents the ANA induced changes in sleep. The present results suggest that a cannabinoid system in the PPTg may be involved in sleep regulation and that the cannabinoid effect is mediated by the CB1 receptor coupled to a PLC second messenger system.
Chapter
The cannabinoid receptor family currently includes twotypes:CB1, characterized in neuronal cells and brain, and CB2, characterized in immune cells and tissues. CB1 and CB2 receptors are members of the superfamily of seven-transmembrane-spanning (7-TM) receptors, having a protein structure defined by an array of seven membrane-spanning helices with intervening intracellular loops and a C-terminal domain that can associate with G proteins. Cannabinoid receptors are associated with G proteins of the Gi/o family (Gi1,2 and 3, and Go1 and 2). Signal transduction via Gi inhibits adenylyl cyclase in most tissues and cells, although signaling via Gs stimulates adenylyl cyclase in some experimental models. Evidence exists for cannabinoid receptor-mediated Ca2+ fluxes and stimulation of phospholipases A and C. Stimulation of CB1 and CB2 cannabinoid receptors leads to phosphorylation and activation of p42/p44 mitogen-activated protein kinase (MAPK), p38 MAPK and Jun N-terminal kinase (JNK) as signaling pathways to regulate nuclear transcription factors. The CB1 receptor regulates K+ and Ca2+ ion channels, probably via Go. Ion channel regulation serves as an important component of neurotransmission modulation by endogenous cannabinoid compounds released in response to neuronal depolarization. Cannabinoid receptor signaling via G proteins results from interactions with the second, third and fourth intracellular loops of the receptor. Desensitization of signal transduction pathways that couple through the G proteins probably entails phosphorylation of critical amino acid residues on these intracellular surfaces.
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Cannabinoids are a class of compound found in marijuana which have been known for their therapeutic and psychoactive properties for at least 4000 years. Isolation of the active principle in marijuana, 9-THC, provided the lead structure in the development of highly potent congeners which were used to probe for the mechanism of marijuana action. Cannabinoids were shown to bind to selective binding sites in brain tissue thereby regulating second messenger formation. Such studies led to the cloning of three cannabinoid receptor subtypes, CB1, CB2, and CB1A all of which belong to the superfamily of G protein-coupled plasma membrane receptors. Analogous to the discovery of endogenous opiates, isolation of cannabinoid receptors provided the appropriate tool to isolate an endogenous cannabimimetic eicosanoid, anandamide, from porcine brain. Recent studies indicate that anandamide is a member of a family of fatty acid ethanolamides that may represent a novel class of lipid neurotransmitters. This review discusses recent progress in cannabinoid research with a focus on the receptors for 9-THC, their coupling to second messenger responses, and the endogenous lipid cannabimimetic, anandamide.
Chapter
Mammalian tissues express at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals where they mediate inhibition of transmitter release. CB2 receptors
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The presence of central cannabinoid receptor (CB1), involving the N-terminal 14 amino acid peptide, was demonstrated in the rat brain by immunohistochemistry. Intensely stained neurons were observed in the principal neurons of the hippocampus, striatum, substantia nigra, cerebellar cortex, including the Purkinje cells. Moderate CB1-IR cell bodies and fibers were present in the olfactory bulb, cingulate, entorhinal and piriform cortical areas, amygdala and nucleus accumbens. The perivascular glial fibers have shown moderate to high density CB1-IR in olfactoric and limbic structures. Low density was detected in the thalamus and hypothalamus and area postrema. The CB1 receptor was widely distributed in the forebrain and sparsely in the hindbrain.These new data support the view that the endogenous cannabinoids play an important role in different neuronal functions as neuromodulators or neurotransmitters.
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In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2—the two cannabinoid receptors identified thus far—with Ki values of 472 ± 55 and 1400 ± 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of Δ9-tetrahydrocannabinol (Δ9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of Δ9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than Δ9-THC.
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Marijuana affects neural functions through the binding of its active component (Delta(9)-THC) to cannabinoid receptors in the CNS. Recent studies have elucidated that endogenous ligands for cannabinoid receptors, endocannabinoids, serve as retrograde messengers at central synapses. Endocannabinoids are produced on demand in activity-dependent manners and released from postsynaptic neurons. The released endocannabinoids travel backward across the synapse, activate presynaptic CB1 cannabinoid receptors, and modulate presynaptic functions. Retrograde endocannabinoid signaling is crucial for certain forms of short-term and long-term synaptic plasticity at excitatory or inhibitory synapses in many brain regions, and thereby contributes to various aspects of brain function including learning and memory. Molecular identities of the CB1 receptor and enzymes involved in production and degradation of endocannabinoids have been elucidated. Anatomical studies have demonstrated unique distributions of these molecules around synapses, which provide morphological bases for the roles of endocannabinoids as retrograde messengers. CB1-knockout mice exhibit various behavioral abnormalities and multiple defects in synaptic plasticity, supporting the notion that endocannabinoid signaling is involved in various aspects of neural function. In this review article, the authors describe molecular mechanisms of the endocannabinoid-mediated synaptic modulation and its possible physiological significance.
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Regulation of the sleep-wake cycle involves diverse brain circuits and molecules. Further complexity has been introduced by the recognition of sleep-promoting factors that accumulate in the brain naturally or during prolonged waking. The variety of sleep-inducing molecules includes peptides, cytokines, and lipids. With regard to the lipids, current evidence indicates the existence of endogenous lipids, called endocannabinoids, that mimic the pharmacological actions of the psychoactive ingredient of marijuana and that are likely to be essential factors in sleep promotion. This Mini-Review presents current knowledge concerning the role of endogenous compounds with sleep-promoting properties.
Article
2-Arachidonoylglycerol (2-AG) is a monoacylglycerol (MAG) molecule containing an esterified arachidonic acid chain at sn-2 position of the glycerol backbone. Together with structurally similar N-arachidonoylethanolamine (anandamide), 2-AG has been extensively studied as an endogenous ligand of cannabinoid receptors (an endocannabinoid) in brain and other mammalian tissues. Accumulating evidence demonstrates that the endocannabinoid system, including the central-type cannabinoid receptor CB1 and 2-AG, is responsible for synaptic retrograde signaling in the central nervous system. As 2-AG is rapidly formed from membrane phospholipids on cellular stimuli and degraded to arachidonic acid and glycerol, the enzymes catalyzing its biosynthesis and degradation are believed to play crucial roles in the regulation of its tissue levels. The major biosynthetic pathway appears to consist of sequential hydrolyses of inositol phospholipids via diacylglycerol (DAG) by β-type phospholipase C and DAG lipase, while MAG lipase is a principal enzyme in the degradation. In this short review, we will briefly outline rapid advances in enzymological research on the biosynthetic and degradative pathways of 2-AG.
Article
GPR55 has recently attracted much attention as another member of the cannabinoid family, potentially explaining physiological effects that are non-CB1/CB2 mediated. However, the data gathered so far are conflicting with respect to its pharmacology. We review the primary literature to date on GPR55, describing its discovery, structure, pharmacology and potential physiological functions. The CB1 receptor antagonist/inverse agonist AM251 has been shown to be a GPR55 agonist in all reports in which it was evaluated, as has the lysophospholipid, lysophosphatidylinositol (LPI). Whether GPR55 responds to the endocannabinoid ligands anandamide and 2-arachidonylglycerol and the phytocannabinoids, delta-9-tetrahydrocannabidiol and cannabidiol, is cell type and tissue-dependent. GPR55 has been shown to utilize G(q), G(12), or G(13) for signal transduction; RhoA and phospholipase C are activated. Experiments with mice in which GPR55 has been inactivated reveal a role for this receptor in neuropathic and inflammatory pain as well as in bone physiology. Thus delineating the pharmacology of this receptor and the discovery of selective agonists and antagonists merits further study and could lead to new therapeutics.
Article
The effects of anandamide transport inhibitor AM404 were investigated on depolarization-induced 45Ca2+ fluxes in transverse tubule membrane vesicles from rabbit skeletal muscle and on Ba2+ currents through L-type voltage-dependent Ca2+ channels in rat myotubes. AM404, at the concentration of 3 microM and higher, caused a significant inhibition of 45Ca2+ fluxes. Radioligand binding studies indicated that the specific binding of [3H]Isradipine to transverse tubule membranes was also inhibited significantly by AM404. In controls and in presence of 10 microM AM404, B(max) values were 51+/-6 and 27+/-5 pM/mg, and KD values were 236+/-43 and 220+/-37 pM, respectively. Inhibitory effects of AEA and arachidonic acid on 45Ca2+ flux and [3H]Isradipine binding reported in earlier studies, were also enhanced significantly in the presence of AM404. In the presence of VDM11 (1 microM), another anandamide transport inhibitor, AM404 continued to inhibit 45Ca2+ fluxes and [3H]Isradipine binding. In rat myotubes, Ca2+ currents through L-type Ca2+ channels recorded in whole-cell configuration of patch clamp technique were inhibited by AM404 in a concentration-dependent manner with an IC50 value of 3.2 microM. In conclusion, results indicate that AM404 inhibits directly the function of L-type voltage-dependent Ca2+ channels in mammalian skeletal muscles.
Article
Regulation of the sleep-waking cycle is complex, involving multiple neurological circuits and diverse endogenous molecules. Interplay among assorted neuroanatomical and neurochemical systems such as acetylcholine, dopamine, noradrenaline, serotonin, histamine, and hypocretin maintain the waking (W) state. The sleep-onset is governed by the interacting forces of the sleep drive, which steadily increases with duration of W, and circadian fluctuations. Sleep-promoting neurons located in the anterior hypothalamus release GABA and inhibit wake-promoting regions in the hypothalamus and brainstem and participate in the generation of slow wave sleep (SWS). During rapid eye movement (REM) sleep, brainstem regions typically inhibited during W and SWS become active. In this regard, ascending projections from cholinergic neurons in the brainstem activate the thalamus which in turn increases the firing of the neurons in the cortex. Finally, sleep-promoting substances that accumulate in the brain during natural or prolonged W implicate a further complexity in the mechanism of modulation of the sleep-wake cycle. This review provides a broad understanding of our present knowledge in the field of sleep research.
Article
Endogenous cannabinoids or endocannabinoids are lipid molecules that have a variety of biological actions, most notably via activation of the cannabinoid receptors. The family of endocannabinoids includes arachidonoylethanolamide (ANA) which modulates different behaviors, such as sleep. However, it is unknown whether pharmacological elevation of ANA endogenous levels might induce sleep. VDM 11 [(5 Z,8 Z,11 Z,14 Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide] is commonly used as an inhibitor of ANA cellular uptake, and thereby to potentiate its actions. In this study we have examined whether VDM-11 exerts any effect on the sleep-wake cycle and c-Fos expression in brain areas. When assayed alone in rats, VDM-11 (10 or 20 microg/5 microL, i.c.v.) at the beginning of the lights-off period, reduced wakefulness and increased sleep. The CB(1) cannabinoid receptor antagonist, SR141716A, partially reversed the effects of VDM-11 on sleep. Additionally, VDM-11 enhanced c-Fos expression in sleep-related brain areas such as the anterior hypothalamic area, paraventricular thalamic nucleus, and pedunculopontine tegmental nucleus. It is concluded that VDM-11 displays sleep-inducing properties and these effects slightly, albeit significantly, are reversed using SR141716A. Furthermore, c-Fos data suggest a possible underlying neuroanatomical substrate of the sleep-inducing properties of VDM-11. We report evidence suggesting that VDM-11 might be considered for the development of new pharmacological and pharmaceutical approaches to treat sleep disorders such as insomnia.
Article
Electroencephalographic readings and eye movement were recorded in experienced marijuana users under placebo and tetrahydrocannabinol (THC). Four subjects were studied for 3 baseline nights, 3 nights under initial dosage of 70 mg/day, the last 3 nights of a 2-wk period of 210 mg/day, and the first 3 nights of withdrawal. Three other subjects were studied only during the latter 2 conditions. Administration of THC significantly reduced eye movement activity during sleep with rapid eye movements (REM) and, to a lesser extent, the duration of REM itself. Withdrawal led to increases above baseline in both measures but the "rebound" effect was greater for eye movement. Stage 4 sleep tended to increase on drug, but this effect was not statistically significant. On withdrawal, stage 4 sleep decreased significantly; this change was marked only on the first withdrawal night. The functional or biological significance of these changes is unclear. Nevertheless, these are the most marked effects of THC on brain electrical activity demonstrated thus far. Since its pattern of effects on sleep appears unique to THC, this drug may prove to be a valuable tool in the elucidation of the pharmacology of sleep. Possible relations between effects on sleep pattern and on behavior are discussed.
Article
Acetylcholine (ACh) in the brain stem has been implicated in the generation of paradoxical sleep (PS). In order to clarify the relationship between local ACh release in the dorsal tegmental field (FTD), a possible PS-generating locus, and sleep-wake states in 6 cats. ACh was measured by the method of in vivo microdialysis and high performance liquid chromatography-electrochemical detection. It is noteworthy that ACh release was about 2 times higher (P less than 0.001) during PS than during slow-wave sleep and wakefulness in FTD, but not in the caudate nucleus, a control region. ACh release in FTD appeared to begin to increase prior to the onset of PS. Electrical and chemical (glutamate) stimulations of the nucleus magnocellularis (MC) enhanced ACh release in FTD and shortened PS latency. These results suggest that this PS-related enhancement of ACh release in FTD is induced by some cholinergic projections from glutamate-receptive neurons in MC.
Article
Persistent behavioral effects resembling those of hippocampal brain lesions have been reported following chronic administration of marijuana or its major psychoactive constituent, delta-9-tetrahydrocannabinol (THC) to rats. We used morphometric techniques to investigate the effects of chronic THC on the anatomical integrity of the hippocampus. Rats dosed orally for 90 days with 10 to 60 mg/kg THC or vehicle were evaluated by light and electron microscopy up to 7 months after their last dose of drug. Electron micrographs revealed a striking ultrastructural appearance and statistically significant decreases in mean volume of neurons and their nuclei sampled from the hippocampal CA3 region of rats treated with the highest doses of THC. A 44% reduction in the number of synapses per unit volume was demonstrated in these same rats. Golgi impregnation studies of additional groups of rats treated with 10 or 20 mg/kg/day THC and sacrificed 2 months after their last treatment with THC revealed a reduction in the dendritic length of CA3 pyramidal neurons, despite normal appearing ultrastructure and no changes in synaptic density. The hippocampal changes reported here may constitute a morphological basis for behavioral effects after chronic exposure to marijuana.
Article
The many studies that have been included in this review suggest that cannabinoids have ubiquitous effects on biological systems. These results also underscore the intensity to which cannabinoids have been studied. While there are numerous reasons for the prodigious amount of cannabinoid research, a major stimulus has been the desire to identify a specific biochemical event or pathway that is responsible for the expression of delta 9-THC's unique psychoactivity. It is the hope that delta 9-THC, as with all centrally acting drugs, might serve as an important tool for achieving a better understanding of the central nervous system. As discussed in this review, the psychoactivity of cannabinoids might best be described as a composite of numerous effects. If that is indeed the case, then it would seem logical that these centrally mediated effects do not arise from a single biochemical alteration, but rather from multiple actions. Of course, a major problem arises when one attempts to establish a relationship between cause and effect when multiple mechanisms and effects are involved. An initial approach to reducing the complexity of elucidation of mechanism of action should involve attempts to distinguish those cannabinoid actions which result in specific effects (psychoactivity) from those which produce non-psychoactive effects (such as general depression). There are several fundamental principles that can be used to assess specificity, including concentration or dose of the drug that is required to produce a given effect. Low doses of delta 9-THC are capable of producing the psychoactivity that is unique to cannabinoids, whereas higher doses may produce effects that are both specific and nonspecific for cannabinoids. Unfortunately, establishing this basic tenet for delta 9-THC has proven to be difficult. It has not been possible to establish the concentration of delta 9-THC at its site of action that is necessary to produce a given pharmacological effect. While it is a simple matter to measure the concentration of cannabinoids in either a whole tissue or an incubation medium, the hydrophobicity of cannabinoids dramatically affects their affinity for, and hence concentration in, the biochemical components of the tissue. If the concentration of delta 9-THC could be measured at its site of action, then the relevance of many of its pharmacological effects could be adequately determined. Two possible mechanisms by which cannabinoids might produce psychoactivity are membrane perturbation and receptor interactions, and indeed, both mechanisms have received considerable attention.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
Marijuana seems firmly established as another social drug in Western countries, regardless of its current legal status. Patterns of use vary widely. As with other social drugs, the pattern of use is critical in determining adverse effects on health. Perhaps the major area of concern about marijuana use is among the very young. Using any drug on a regular basis that alters reality may be detrimental to the psychosocial maturation of young persons. Chronic use of marijuana may stunt the emotional growth of youngsters. Evidence for an amotivational syndrome is largely based on clinical reports; whether marijuana use is a cause or effect is uncertain. A marijuana psychosis, long rumored, has been difficult to prove. No one doubts that marijuana use may aggravate existing psychoses or other severe emotional disorders. Brain damage has not been proved. Physical dependence is rarely encountered in the usual patterns of social use, despite some degree of tolerance that may develop. The endocrine effects of the drug might be expected to delay puberty in prepubertal boys, but actual instances have been rare. As with any material that is smoked, chronic smoking of marijuana will produce bronchitis; emphysema or lung cancer have not yet been documented. Cardiovascular effects of the drug are harmful to those with preexisting heart disease; fortunately the number of users with such conditions is minimal. Fears that the drug might accumulate in the body to the point of toxicity have been groundless. The potential deleterious effects of marijuana use on driving ability seem to be self-evident; proof of such impairment has been more difficult. The drug is probably harmful when taken during pregnancy, but the risk is uncertain. One would be prudent to avoid marijuana during pregnancy, just as one would do with most other drugs not essential to life or well-being. No clinical consequences have been noted from the effects of the drug on immune response, chromosomes, or cell metabolites. Contamination of marijuana by spraying with defoliants has created the clearest danger to health; such attempts to control production should be abandoned. Therapeutic uses for marijuana, THC, or cannabinoid homologs are being actively explored. Only the synthetic homolog, nabilone, has been approved for use to control nausea and vomiting associated with cancer chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
This study was designed to determine the acute effects of delta 9-THC on the cortical EEG with the spectral analysis technique. Adult female Sprague-Dawley rats were implanted with chronic cortical and temporalis muscle electrodes. Intraperitoneally administered delta 9-THC (5 and 10 mg/kg) produced a reduction in peak-to-peak voltage of the desynchronized cortical EEG during wakefulness. Associated spectral power was reduced to about 50% of control during the first hour after injection of delta 9-THC and gradually returned toward the control value over an 8-hr period. Occurrences of delta 9-THC-induced high-voltage EEG bursts, overriding the reduced EEG tracing, were associated with an EEG spectral peak at 6 Hz. The first few slow-wave sleep (SWS) episodes appearing after delta 9-THC administration were associated with more slow-frequency waveforms and more slow-frequency spectral power than with control slow-wave sleep episodes. During control rapid eye movement (REM) sleep episodes, an EEG theta wave pattern, with an associated spectral peak at about 8 Hz, was characteristic. Conversely, the first few REM sleep episodes emerging after delta 9-THC administration contained overriding high-voltage bursts, the related power spectra of which had two peaks at about 7 and 11 Hz.
Article
This study describes the effect of two weeks of delta-9-tetrahydrocannabinol (THC) administration upon normal sleep. The two subjects, two brothers in their 20s, slept in the laboratory for 27 consecutive nights and then, after four nights at home, for four additional nights. One subject, after an adaption night, received placebo for four baseline nights, 30 mg of THC for the next 14 nights, and placebo during four withdrawal nights. The other subject received placebo during this entire period. One year later the subjects alternated these conditions. The subjects had difficulty falling and staying asleep during the first two nights of placebo after 14 consecutive drug nights. This mild drug withdrawal insomnia was not accompanied by the increase of REM sleep which frequently accompanies withdrawal of other drugs. Starting after about a week of THC administration, and continuing for a week after drug discontinuance, there was a marked decrease in the type of sleep associated with slow waves in the electroencephalogram, nonREM sleep stages 3 and 4. The fact that prolonged, but not acute use, suppresses slow wave sleep indicates that this commonly used drug produces a poorly understood change in brain physiology.
Article
1. Effects of cannabinoid agonists on the serotonin (5-HT)3 receptor-mediated current were investigated in rat nodose ganglion neurons. Anandamide, Win 55212-2, and CP55940 inhibited the 5-HT-induced current in a concentration dependent manner. IC50 values were 190, 310, and 94 nM for anandamide, Win 55212-2, and CP55940, respectively, and 1.6 microM for the nonpsychoactive enantiomer CP56667. This inhibition was slowly developing, noncompetitive, not dependent on membrane potential, and not affected by adenosine 3',5'-cyclic monophosphate (cAMP) analogues, guanosine-5'-O-(2-thiodiphosphate) (GDP-beta-S), and opioid receptor antagonist naltrexone. These data suggest that 5-HT3 receptor ion-channel is a site acted upon by cannabinoid agonists in the nervous system, and the action of cannabinoid agonists on 5-HT3 receptors may be a possible mechanism for some of the behavioral effects of cannabinoids, such as antiemesis and analgesia.
Article
We have reported that marihuana and its principal psycoactive compound, delta 9-tetrahydrocannabinol (delta 9-THC) produce alterations in several cerebral areas after acute treatment. Based on the involvement of 5-hydroxytryptamine (5-HT) on memory and learning and the reported effects of delta 9-THC on short-term memory, we designed an experiment to evaluate the memory performance and its possible relationship with serotonergic alterations after delta 9-THC administration. Male Wistar rats received an acute oral dose of THC (5 mg/kg). Short-Term memory was tested on a radial 8-arm maze with a 5 s delay, after 35 days of training. The animals were food deprived and adjusted for growth. 5-HT and its metabolite, 5-HIAA, levels were measured in cerebral cortex, dorsal hippocampus, ventral hippocampus, rostral neoestriatum and amygdala basal nucleus, by HPLC-ED. The experiment indicates an impairment of short-term memory in the radial maze test after delta 9-THC administration. The control group performed the test without errors, while the treated group made a significant number of errors (Z = 0.019, Mann-Whitney test). This behavioral effect did not seem to be related to serotonergic alterations, as the 5-HT turnover rate was not different between treated and control animals.
Article
Previous autoradiographic studies in rats using [3H]CP55,940 have demonstrated the cannabinoid receptor to be located on the axon terminals of striatal efferent neurons projecting to the globus pallidus and substantia nigra. Because these neurons are selectively lost in Huntington's disease, a loss of [3H]CP55,940 binding is predicted in the substantia nigra of the Huntington's disease brain. We have used autoradiography to compare the binding of [3H]CP55,940 in the substantia nigra of Huntington's disease and neurologically normal brains. The results have demonstrated that cannabinoid receptors in the normal human substantia nigra are discreetly localized within the substantia nigra pars reticulata. In contrast, the Huntington's disease brains show a massive loss (97.5%) of cannabinoid receptor binding in the substantia nigra pars reticulata. These results show that in the substantia nigra of the human brain cannabinoid receptors are located on striatonigral terminals which degenerate in Huntington's disease.
Article
Anandamide (arachidonyl ethanolamide) has been identified as an endogenous ligand of cannabinoid receptors on the basis of its ability to displace 3H-labeled synthetic cannabinoid in a binding assay. One well characterized cellular action of cannabinoids is inhibition of hormonally stimulated adenylyl cyclase. Another action of synthetic cannabinoids is potent, stereospecific, and reversible inhibition of N-type calcium currents (ICa) in the NG108-15 neuroblastoma-glioma cell line via a pertussis toxin (PTX)-sensitive pathway, independently of cAMP metabolism. Here we used the N18 neuroblastoma cell line and the whole-cell voltage-clamp technique to show that anandamide also potently inhibits N-type ICa in a PTX-sensitive fashion. As with the cannabinomimetic aminoalkylindole WIN 55,212-2, inhibition by anandamide was voltage dependent and N-ethylmaleimide sensitive. However, anandamide was less efficacious than either WIN 55,212-2 or the nonclassical cannabinoid CP 55,940. Indeed, anandamide appears to act as a partial agonist at the cannabinoid receptor. Application of WIN 55,212-2 always caused further inhibition of ICa in cells exposed to a maximally effective concentration of anandamide, and application of anandamide always caused a partial recovery of ICa in cells exposed to a maximally effective concentration of WIN 55,212-2. This partial agonist property of anandamide suggests that, although anandamide inhibits N-type ICa via a PTX-sensitive G protein, its action as a neuromodulator in the intact animal may be more complex than would be inferred by extrapolating the results of in vivo studies with (-)-delta 9-tetra-hydrocannabinol or synthetic cannabinoids.
Article
The effects of the central (CB1) cannabinoid receptor antagonist SR 141716A on the sleep-waking cycle were investigated in freely-moving rats using time scoring and power spectral analysis of the electroencephalogram (EEG). Over a 4-hour recording period, SR 141716A (0.1, 0.3, 1, 3, and 10 mg/kg I.P.) dose-dependently increased the time spent in wakefulness at the expense of slow-wave sleep (SWS) and rapid eye movement sleep (REMS), delayed the occurrence of REMS but did not change the mean duration of REMS episodes. Moreover, the compound induced no change in motor behavior. At the efficient dose of 3 mg/kg I.P., SR 141716A reduced the spectral power of the EEG signals typical of SWS but did not affect those of wakefulness. Taken together, these results demonstrate that the EEG effects of SR 141716A reflect arousal-enhancing properties. In addition, the present study suggests that an endogenous cannabinoid-like system is involved in the control of the sleep-waking cycle.
Article
Anandamide (arachidonylethanolamide) is a novel lipid neurotransmitter first isolated from porcine brain which has been shown to be a functional agonist for the cannabinoid CB1 and CB2 receptors. Anandamide has never been isolated from human brain or peripheral tissues and its role in human physiology has not been examined. Anandamide was measured by LC/MS/MS and was found in human and rat hippocampus (and human parahippocampal cortex), striatum, and cerebellum, brain areas known to express high levels of CB1 cannabinoid receptors. Significant levels of anandamide were also found in the thalamus which expresses low levels of CB1 receptors. Anandamide was also found in human and rat spleen which expresses high levels of the CB2 cannabinoid receptor. Small amounts of anandamide were also detected in human heart and rat skin. Only trace quantities were detected in pooled human serum, plasma, and CSF. The distribution of anandamide in human brain and spleen supports its potential role as an endogenous agonist in central and peripheral tissues. The low levels found in serum, plasma, and CSF suggest that it is metabolized in tissues where it is synthesized, and that its action is probably not hormonal in nature.