Article

Anandamide Enhances Extracellular Levels of Adenosine and Induces Sleep: An In Vivo Microdialysis Study

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  • Universidad Anáhuac Mayab. Mérida, Yucatán. México
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Abstract

The principal component of marijuana, delta-9-tetrahydrocannabinol increases sleep in humans. Endogenous cannabinoids, such as N-arachidonoylethanolamine (anandamide), also increase sleep. However, the mechanism by which these molecules promote sleep is not known but might involve a sleep-inducing molecule such as adenosine. Microdialysis samples were collected from the basal forebrain in order to detect levels of adenosine before and after injection of anandamide. Rats were implanted for sleep studies, and a cannula was placed in the basal forebrain to collect microdialysis samples. Samples were analyzed using high-performance liquid chromatography. Basic neuroscience research laboratory. Three-month-old male F344 rats. At the start of the lights-on period, animals received systemic injections of dimethyl sulfoxide (vehicle), anandamide, SR141716A (cannabinoid receptor 1 [CB1] antagonist), or SR141716A and anandamide. One hour after injections, microdialysis samples were collected (5 microL) from the basal forebrain every hour over a 20-minute period for 5 hours. The samples were immediately analyzed via high-performance liquid chromatography for adenosine levels. Sleep was also recorded continuously over the same period. Anandamide increased adenosine levels compared to vehicle controls with the peak levels being reached during the third hour after drug injection. There was a significant increase in slow-wave sleep during the third hour. The induction in sleep and the rise in adenosine were blocked by the CB1-receptor antagonist, SR141716A. Anandamide increased adenosine levels in the basal forebrain and also increased sleep. The soporific effects of anandamide were mediated by the CB1 receptor, since the effects were blocked by the CB1-receptor antagonist. These findings identify a potential therapeutic use of endocannabinoids to induce sleep in conditions where sleep may be severely attenuated.

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... AEA is primarily inactivated via fatty acid amide hydrolase (FAAH), and 2-AG signaling is terminated by monoacyglycerol lipase (MAGL). Of the relatively few studies that have been performed, administration of exogenous AEA consistently increases rapid eye movement (REM) sleep and non-REM (NREM) sleep [13][14][15][16]. However, conflicting results arise from attempts to increase endogenous AEA levels. ...
... However, studies with constitutive knockout mice are always subject to confounds arising from developmental adaptations, and this has been confirmed for the CB1 knockout mice used in these studies [26,27]. On the other hand, studies with CB1 antagonists in rodents have had conflicting results with some reporting a weak reduction in NREM sleep [15,19,[28][29][30] and others finding no effects on sleep [13,31,32]. Of note, all of these studies were performed over short time windows (< 8 Hr recordings), and eCB levels are known to fluctuate over the circadian cycle [33,34]. ...
... These data would appear to suggest that N-acylethanolamines are not important for the regulation of vigilance states. However, application of exogenous AEA is known to facilitate NREM sleep [14,15], and the elevation of N-acylethanolamines in rodent brain tissue by URB lasts only a few hours [48]. Thus, we performed a separate experiment with a single dose of the selective, long-lasting FAAH inhibitor AM3506 (10.0 mg/kg; Fig 8A) that reduces FAAH activity for up to 10 days after administration [49]. ...
Article
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The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized. We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system. Rapid, unbiased scoring of vigilance states was achieved using an automated algorithm that we devised and validated. Increasing endocannabinoid tone with a selective inhibitor of monoacyglycerol lipase (JZL184) or fatty acid amide hydrolase (AM3506) produced a transient increase in non-rapid eye movement (NREM) sleep due to an augmentation of the length of NREM bouts (NREM stability). Similarly, direct activation of type 1 cannabinoid (CB1) receptors with CP47,497 increased NREM stability, but both CP47,497 and JZL184 had a secondary effect that reduced NREM sleep time and stability. This secondary response to these drugs was similar to the early effect of CB1 blockade with the antagonist/inverse agonist AM281, which fragmented NREM sleep. The magnitude of the effects produced by JZL184 and AM281 were dependent on the time of day this drug was administered. While activation of CB1 resulted in only a slight reduction in gamma power, CB1 blockade had dramatic effects on broadband power in the EEG, particularly at low frequencies. However, CB1 blockade did not significantly reduce the rebound in NREM sleep following total sleep deprivation. These results support the hypothesis that endocannabinoid signaling through CB1 is necessary for NREM stability but it is not necessary for sleep homeostasis.
... 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). In addition, CB1 knockout mice experience increased wakefulness (9). ...
... In addition, CB1 knockout mice experience increased wakefulness (9). The relationship between CB1 receptor inactivation and wakefulness is likely related to anandamide (AEA), an endogenous cannabinoid that, like THC, binds to the CB1 receptor and promotes sleep, including increased slow wave sleep (SWS) and REM time (6,(10)(11)(12)(13). AEA is degraded by the enzyme, fatty acid amide hydrolase (FAAH). ...
... Our findings that FAAH A Carriers reported better sleep quality aligns with animal literature showing that increased endocannabinoid activity promotes sleep (6,(10)(11)(12)(13). Although we are not aware of other human studies investigating the relationship between endocannabinoid genes and sleep, one study reported a significantly greater decrease in fatigue for FAAH C/C genotypes after 10mg amphetamine administration compared to A carriers (75). ...
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.
... Lastly, several pieces of evidence have shown that anandamide membrane transporter (AMT) also displays a key role in modulating multiple biological functions (Leung et al., 2013;Nicolussi and Gertsch, 2015). Among the diverse findings that suggest the involvement of the endocannabinoid system in regulating several neurobiological phenomena, different reports have indicated that the sleep-wake cycle is likely under control of this system (Santucci et al., 1996;Murillo-Rodríguez et al., 1998, 2003, 2008a, 2011aHerrera-Solis et al., 2010;Rueda-Orozco et al., 2010;Pava et al., 2014Pava et al., , 2016). Due to recent results regarding the relationship between AEA and the transient receptor potential cation channel subfamily V member 1 (TRPV1) also known as the capsaicin receptor or vanilloid receptor 1, increasing scientific interest is addressing the neuromolecular properties of TRPV1 (Tóth et al., 2009;Lowin and Straub, 2015;Chen et al., 2016;Kirkedal et al., 2016). ...
... AA-5-HT was provided by Prof. Vincenzo Di Marzo and chemical was dissolved in a vehicle (VEH) solution composed of polyethylene-glycol/saline (5:95 v/v) as described previously (Murillo-Rodríguez et al., 2003, 2011a). All reagents, chemicals, and materials were purchased from Sigma–Aldrich (St Louis, MO, United States). ...
... The endocannabinoid system exerts multiple and complex modulatory physiological functions (Kendall and Yudowski, 2016;Ligresti et al., 2016;Argueta and DiPatrizio, 2017;Bennett et al., 2017;Dos Anjos-Garcia et al., 2017;Sun et al., 2017). For instance, cumulative evidence has suggested that the elements of the endocannabinoid system, including FAAH, control the sleepwake cycle (Santucci et al., 1996;Murillo-Rodríguez et al., 1998, 2003, 2008a, 2011aHerrera-Solis et al., 2010;Rueda-Orozco et al., 2010;Pava et al., 2014Pava et al., , 2016). In this regard, an experimental approach to explore the role of FAAH in sleep modulation has consisted in the characterization of the properties of FAAH inhibitors, such as URB597 (Murillo-Rodríguez et al., 2007b, 2011a). ...
Article
The endocannabinoid system comprises several molecular entities such as endogenous ligands [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], receptors (CB 1 and CB 2), enzymes such as [fatty acid amide hydrolase (FAHH) and monoacylglycerol lipase (MAGL)], as well as the anandamide membrane transporter. Although the role of this complex neurobiological system in the sleep–wake cycle modulation has been studied, the contribution of the blocker of FAAH/transient receptor potential cation channel subfamily V member 1 (TRPV1), N-arachidonoyl-serotonin (AA-5-HT) in sleep has not been investigated. Thus, in the present study, varying doses of AA-5-HT (5, 10, or 20 mg/Kg, i.p.) injected at the beginning of the lights-on period of rats, caused no statistical changes in sleep patterns. However, similar pharmacological treatment given to animals at the beginning of the dark period decreased wakefulness (W) and increased slow wave sleep (SWS) as well as rapid eye movement sleep (REMS). Power spectra analysis of states of vigilance showed that injection of AA-5-HT during the lights-off period diminished alpha spectrum across alertness in a dose-dependent fashion. In opposition, delta power spectra was enhanced as well as theta spectrum, during SWS and REMS, respectively. Moreover, the highest dose of AA-5-HT decreased wake-related contents of neurotransmitters such as dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT) whereas the levels of adenosine (AD) were enhanced. In addition, the sleep-inducing properties of AA-5-HT were confirmed since this compound blocked the increase in W caused by stimulants such as cannabidiol Frontiers in Molecular Neuroscience | www.frontiersin.org 1 May 2017 | Volume 10 | Article 152 Murillo-Rodríguez et al. Injections of N-Arachidonoyl-Serotonin (AA-5-HT) Increase Sleep (CBD) or modafinil (MOD) during the lights-on period. Additionally, administration of AA-5-HT also prevented the enhancement in contents of DA, NE, EP, 5-HT and AD after CBD of MOD injection. Lastly, the role of AA-5-HT in sleep homeostasis was tested in animals that received either CBD or MOD after total sleep deprivation (TSD). The injection of CBD or MOD increased alertness during sleep rebound period after TSD. However, AA-5-HT blocked this effect by allowing animals to display an enhancement in sleep across sleep rebound period. Overall, our findings provide evidence that AA-5-HT is an important modulator of sleep, sleep homeostasis and neurotransmitter contents.
... It has been reported that both VDM-11 and OMDM-2 (selective inhibitors of endocannabinoid uptake) induce sleep by promoting the endogenous accumulation of AEA [66]. Previous studies have shown the sleep-promoting effects of AEA [68,69]. It has been shown that URB597 enhances wakefulness and decreases SWS and REM sleep in rats [70,71]. ...
... AEA via activating CB1r increases spontaneous bursting and oscillatory activity in the thalamus and induces a general hyperpolarization in the dorsal lateral geniculate nucleus, indicating the role of CB1r in the sleep-wake cycle and the level of arousal [81]. AEA promotes SWS probably via increasing extracellular adenosine concentrations [69]. It has been reported that sleep-inducing effects of cannabinoids may be related to adenosine [69]. ...
... AEA promotes SWS probably via increasing extracellular adenosine concentrations [69]. It has been reported that sleep-inducing effects of cannabinoids may be related to adenosine [69]. Adenosine acts as an endogenous sleep factor and sleep is hypothesized to result from accumulating adenosine levels [69]. ...
Article
Cannabis sativa (Marijuana) has a long history as a medicinal plant and Δ9-tetrahydrocannabinol (Δ9-THC) is the most active component in this plant. Cannabinoids are interesting compounds with various modulatory effects on physiological processes and cognitive functions. The use of cannabinoids is a double-edged sword, because they induce both adverse and therapeutic properties. One of the most important roles of cannabinoids is modulating sleep-wake cycle. Sleep, its cycle, and its mechanism are highly unknown. Also, the effects of cannabinoids on sleep-wake cycle are so inconsistent. Thus, understanding the role of cannabinoids in modulating sleep-wake cycle is a critical scientific goal. Cannabinoids interact with many neurotransmitter systems. In this review article, we chose serotonin due to its important role in regulating sleep-wake cycle. We found that the interaction between cannabinoids and serotonergic signaling especially in the dorsal raphe is extensive, unknown, and controversial.
... Por ejemplo, posteriormente nuestro grupo evaluó el efecto de ANA sobre los niveles de adenosina, un factor inductor de sueño. La administración sistémica de ANA en ratas inducía, además del efecto en el sueño reportado anteriormente (un incremento en el sueño), un aumento en las concentraciones de adenosina colectadas mediante la técnica de microdiálisis y analizadas a través del HPLC 86 . Encontramos además una correlación entre el aumento del sueño y el incremento de adenosina en el cerebro basal de las ratas tratadas con ANA. ...
... Encontramos además una correlación entre el aumento del sueño y el incremento de adenosina en el cerebro basal de las ratas tratadas con ANA. Interesantemente ambos efectos fueron bloqueados con el SR141716A, confirmando que el efecto inductor de sueño ocasionado por ANA era a través del receptor CB 1 86 . Además, el resultado de dicho estudio sugería que el aumento en el sueño ocasionado por ANA podía deberse a la liberación del factor inductor de sueño adenosina 86 . ...
... Interesantemente ambos efectos fueron bloqueados con el SR141716A, confirmando que el efecto inductor de sueño ocasionado por ANA era a través del receptor CB 1 86 . Además, el resultado de dicho estudio sugería que el aumento en el sueño ocasionado por ANA podía deberse a la liberación del factor inductor de sueño adenosina 86 . ...
Article
During the 90s, transmembranal proteins were described as the principal compounds of mariguana, delta-9-tetrahydrocannabinol (Δ 9-THC). These receptors were classified as central or peripheral in base to neuroanatomical localization. They were named CB 1 y CB 2. Later, several endogenous compounds were described as natural agonist for those receptors. Up to now, the presence in the central specific lipids that bind naturally to the CB 1/CB 2 nervous system receptors as been documented. Injection of these compounds induce cannabimimetic effects. Anandamide (ANA), 2-araquidonylglicerol (2-AG), virodhamine (VIR), noladinether (NE) y N-arachidonyldopamine (NADA) are currently molecules that belong to the family of endocannabinoids. The system of the endogenous cannabinoids, or endocannabinoids, is present in the CNS of several species, including the humanone. The system of endocannabinoids includes receptors, endogenous ligands, and enzymes. Since ANA was the first endocannabinoid described, it has been the most studied so far. Pharmacological experiments have shown that this lipid induces several intracellular and behavioral changes. No solid evidence is available up to now about the physiological properties of 2-AG, VIR, NE y NADA. The endocannabinoids have an active role modulating diverse neurobiological functions, such as learning and memory, feeding, pain perception and sleep generation. In the present work, the principal elements of the system of the endocannabinoids as well as their physiological function in the modulation of the state of alertness will be reviewed.
... Then we analysed the effects of CBD on c-Fos immunoreactivity followed by measurement of DA extracellular levels collected from nucleus accumbens (AcbC) using microdialysis and HPLC. Finally, we looked into the Abbreviations: ANA, anandamide; ACSF, artificial cerebrospinal fluid; D 9 -THC, D 9 -tetrahydrocannabinol; CBD, cannabidiol; DA, dopamine; DMH, dorsomedial hypothalamic nucleus; DRD, dorsal raphe nucleus; FAAH, fatty acid amide hydrolase; HVA, homovanillic acid; icv, intracerebroventricular; MPO, medial preoptic nucleus; NA, noradrenaline; AcbC, nucleus accumbens; OEA, oleoylethanolamide; REMS, rapid eye movement sleep; 5-HT, serotonin; SWS, slow wave sleep; W, wakefulness; 5-HIAA, 5-hydroxy-indoleacetic acid; L L-DOPA, 3,4-dihydroxy-L L-phenylalanine possibility that anandamide (ANA) could block the alertness induced by CBD as we have previously reported that the endocannabinoid ANA increases sleep [26][27][28]. ...
... During this period artificial cerebrospinal fluid (ACSF, composition: NaCl (147 mM), KCl (3 mM), CaCl (1.2 mM), MgCl (1.0 mM), pH 7.2) was perfused through a FEP Teflon Tubing (0.65 mm OD · 0.12 mm ID) continuously using a 2.5 ml gastight syringe. All procedures have been reported previously [28]. A syringe pump (CMA/100) controlled the speed of perfusion of the ACSF (flow rate: 1 ll/min). ...
... waking-inducing properties of CBD As found in our previous experiments [26][27][28], ANA substantially decreased waking and increased total sleep time. Administration of ANA 15 min before CBD did not block either the wake-inducing effect caused by CBD or the diminution in SWS (F = 22.472; DF = 20; P < 0.0001; Fig. 7). ...
... Anandamide administered to the cerebral ventricles in male rats decrease waking, increases SWS, and increases REM (Murillo-Rodr{ guez et al. 1998, 2001. Systemic injection of anandamide also decreases waking and increases SWS (Murillo-Rodriguez et al. 2003) and prolonged pentobarbital-induced sleep time (Watanabe et al. 1999). Some of the effects of anandamide on sleep stages appear to be mediated by CB 1 receptors, as the effects on waking, SWS, and REM are blocked by administration of the CB 1 receptor antagonist SR141716 (Murillo-Rodríguez et al. 2001. ...
... The effects of anandamide may involve the activity of phospholipase C (Murillo-Rodríguez et al. 2001). Anandamide administration was associated with an accumulation of adenosine in the lateral preoptic area, which may inhibit cholinergic wake-active neurons (Murillo-Rodriguez et al. 2003). ...
... Compound 64, a potent and selective CB 1 receptor inverse agonist, decreased REM and NREM sleep in rats while increasing wakefulness (Jacobson et al. 2011). SR141716A, a CB 1 receptor antagonist/inverse agonist, increased wakefulness at the expense of SWS and REM sleep, delayed the occurrence of REM sleep, and decreased EEG spectral power during SWS, in part, by increasing adenosine (Murillo-Rodriguez et al. 2003;Jacobson et al. 2011;Santucci et al. 1996). However, other studies using SR141716A showed no effect on sleep parameters (Mendelson and Basile 1999;Navarro et al. 2003). ...
Chapter
The cannabinoids are a family of chemical compounds that can be either synthesized or naturally derived. These compounds have been shown to modulate a wide variety of biological processes. In this chapter, the studies detailing the effects of cannabinoids on sleep in laboratory animals are reviewed. Both exogenous and endogenous cannabinoids generally appear to decrease wakefulness and alter rapid eye movement (REM) and non-REM sleep in animal models. In addition, cannabinoids potentiate the effects of sedative-hypnotic drugs. However, the individual contributions of each cannabinoid on sleep processes is more nuanced and may depend on the site of action in the central nervous system. Many studies investigating the mechanism of cannabinoid effects on sleep suggest that the effects of cannabinoids on sleep are mediated via cannabinoid receptors; however, some evidence suggests that some sleep effects may be elicited via non-cannabinoid receptor-dependent mechanisms. More research is necessary to fully elucidate the role of each compound in modulating sleep processes.
... In general, it has been demonstrated that injections of anandamide generate sleep [125-127, 138, 142], whereas administration of the CB 1 cannabinoid receptor antagonist increases wakefulness (W); [126,127,129,139]. In parallel, FAAH inhibition enhances W and decreases slow wave sleep (SWS) as well as rapid eye movement sleep (REMS; [128,130]). Complementary evidence has indicated that blocking AMT activity promotes sleep [129,131]. ...
... Patients with this illness report higher occurrence of nightmares [182][183][184]. Importantly, pharmacological manipulation of the endocannabinoid system, such as injections of anandamide or blocking the activity of the AMT, increases REMS [125][126][127][128][129][130][131][132][133][134][135][136][137][138]140]. ...
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.
... Systemic administration of AEA in rats induces both an increase in adenosine in the basal forebrain and NREM sleep 3 h after its injection. No changes in REM sleep were reported (Murillo-Rodriguez et al., 2003). Regarding AEA and sleep in humans, there are confounding results. ...
... PEA exhibit a similar effect when injected into the lateral hypothalamus and the dorsal raphe nucleus. Regarding NREM sleep, some observations indicate that AEA facilitates the release of adenosine (Murillo-Rodriguez et al., 2003) in the anterior hypothalamus, a region known to be facilitating NREM sleep. This seems to be one mechanism of action of eCBs to induce NREM sleep. ...
... There are two primary mechanisms proposed to explain this impact. First, endogenous cannabinoids have been shown to increase the level of adenosine, a sleep-promoting agent [11]. Second, neurons in the lateral hypothalamus involved in regulation of arousal systems express CB1 receptors, resulting in inhibition of the arousal system [11]. ...
... First, endogenous cannabinoids have been shown to increase the level of adenosine, a sleep-promoting agent [11]. Second, neurons in the lateral hypothalamus involved in regulation of arousal systems express CB1 receptors, resulting in inhibition of the arousal system [11]. Some studies have shown that immediate administration of Δ 9 -THC reduces sleep latency [12]. ...
Article
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Cannabis may be used, among certain individuals, for its actual and/or perceived sleep-promoting properties. While evidence suggests that cannabis is likely beneficial for sleep initiation, over time individuals may develop tolerance to these benefits, leading to greater use in order to maintain the same sleep-inducing effects. This form of use likely contributes to the development of problematic cannabis use patterns, including cannabis use disorders. Evidence also points to sleep as an important consideration in terms of understanding cannabis withdrawal and relapse. Here, sleep disturbances have been reported as a primary symptom of withdrawal; with studies revealing that this increase in sleep disruption during cannabis discontinuation may be a significant risk factor for relapse. Therefore, interventions aimed at providing alternative means to cope with and/or treat sleep disturbances (e.g., behavioral or pharmacological approaches) are likely important to consider as adjuncts to interventions for cannabis use disorders to improve treatment outcomes.
... 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.
... This system plays a significant role in a wide range of physiologic processes and behaviors including neurogenesis, neural development, immune function, metabolism and energy homeostasis, synaptic plasticity and learning, pain, emotional state, arousal and sleep, stress reactivity, and reward processing/addiction to other drugs of abuse. 12,[14][15][16] In the brain, the endocannabinoid system makes up an extensive interconnected network of neuromodulators that control (usually inhibit) synaptic neurotransmitter release (for review see Refs [12,17]). Endocannabinoids are arachidonic acid derivatives that are released by postsynaptic neurons to regulate presynaptic activity. ...
Chapter
Cannabis has been cultivated and used by humans for thousands of years. Research for decades was focused on understanding the mechanisms of an illegal/addictive drug. This led to the discovery of the vast endocannabinoid system. Research has now shifted to understanding fundamental biological questions related to one of the most widespread signaling systems in both the brain and the body. Our understanding of cannabinoid signaling has advanced significantly in the last two decades. In this review, we discuss the state of knowledge on mechanisms of Cannabis signaling in the brain and the modulation of key brain neurotransmitter systems involved in both brain reward/addiction and psychiatric disorders. It is highly probable that various cannabinoids will be found to be efficacious in the treatment of a number of psychiatric disorders. However, while there is clearly much potential, marijuana has not been properly vetted by the medical-scientific evaluation process and there are clearly a range of potentially adverse side-effects—including addiction. We are at crossroads for research on endocannabinoid function and therapeutics (including the use of exogenous treatments such as Cannabis). With over 100 cannabinoid constituents, the majority of which have not been studied, there is much Cannabis research yet to be done. With more states legalizing both the medicinal and recreational use of marijuana the rigorous scientific investigation into cannabinoid signaling is imperative.
... 153 On the other hand, activation of CB 1 receptors by the endocannabinoid anandamide enhances forebrain adenosine levels with implications for sleep control. 154 Some studies have also highlighted the role of A 2A receptors in the rewarding and reinforcing effects of cannabinoids. The A 2A receptors were found to be important for the rewarding effects of THC administration and the somatic effects of THC withdrawal. ...
Article
A1 and CB1 receptors are main targets for the cognitive effects of caffeine and Δ9-tetrahydrocannabinol (THC), two of the most heavily consumed psychoactive substances worldwide. Both receptors can coincide in the same neuronal structures and both couple to similar G proteins and transducing pathways. Ex vivo evidence revealed that A1 and CB1 receptors can interact, and recent in vivo studies showed that those interactions can influence the behavioral actions of cannabinoids. In particular, studies on interactions between the adenosine receptor nonselective antagonist caffeine and CB1 receptor agonists, such as THC, showed that these receptor interactions may have relevant consequences for the function of the hippocampus, which impact upon cognition. In addition, interactions between adenosine A2A receptors, also targeted by caffeine, and CB1 receptors may impact upon the motor and addictive actions of cannabinoids. Being so widely consumed, caffeine habits should therefore be taken into account whenever evaluating the influences of cannabinoids upon neuronal function or dysfunction in humans. Manipulation of the degree of activation of adenosine receptors with caffeine or adenosine receptor selective ligands should also be considered to reduce side effects of CB1 receptor ligands with therapeutic potential.
... The animals were allowed to habituate and stabilize overnight prior to sample collection. For each experiment, rats were evenly assigned to experimental and control groups (15 rats/group) based on previous studies indicating an effective group size of n ≥ 6 (Murillo- Rodriguez et al. 2003;Walker et al. 2013;unpublished results). Up to 10 animals evenly distributed among experimental and control groups were assessed simultaneously in single daily recording sessions such that final group n's ranged from 8 to 15 subjects may be reached within subsequent recording sessions not exceeding a total of five consecutive daily recording sessions. ...
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Chronic insomnia is defined as a persistent difficulty with sleep initiation maintenance or non-restorative sleep. The therapeutic standard of care for this condition is treatment with gamma-aminobutyric acid (GABA)A receptor modulators, which promote sleep but are associated with a panoply of side effects, including cognitive and memory impairment. Dual orexin receptor antagonists (DORAs) have recently emerged as an alternative therapeutic approach that acts via a distinct and more selective wake-attenuating mechanism with the potential to be associated with milder side effects. Given their distinct mechanism of action, the current work tested the hypothesis that DORAs and GABAA receptor modulators differentially regulate neurochemical pathways associated with differences in sleep architecture and cognitive performance induced by these pharmacological mechanisms. Our findings showed that DORA-22 suppresses the release of the wake neurotransmitter histamine in the lateral hypothalamus, prefrontal cortex, and hippocampus with no significant alterations in acetylcholine levels. In contrast, eszopiclone, commonly used as a GABAA modulator, inhibited acetylcholine secretion across brain regions with variable effects on histamine release depending on the extent of wakefulness induction. In normal waking rats, eszopiclone only transiently suppressed histamine secretion, whereas this suppression was more obvious under caffeine-induced wakefulness. Compared with the GABAA modulator eszopiclone, DORA-22 elicits a neurotransmitter profile consistent with wake reduction that does not impinge on neurotransmitter levels associated with cognition and rapid-eye-movement sleep. This article is protected by copyright. All rights reserved.
... Sleep stages were classified visually as follows: The presence of low amplitude-high frequency in the EEG/EMG activity displaying high values, and alpha power spectra showing higher values was the criteria to identify W. Next, SWS was characterized by high amplitude-slow frequency in the EEG activity which was coupled to low EMG activity and high delta power compared to W, and REMS were identified by the presence of regular theta activity in the EEG signal, and a low to absent EMG signal relative to SWS and W. This criterion was previously reported by our group [29,30]. Sleep scoring was carried out by a single examiner blinded to the treatment of the animals. ...
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The sleep disorder narcolepsy is now considered a neurodegenerative disease because there is a massive loss of neurons containing the neuropeptide hypocretin/orexin (HCRT). In consequence, narcoleptic patients have very low cerebrospinal fluid (CSF) levels of HCRT. Studies in animal models of narcolepsy have shown the neurophysiological role of the HCRT system in the development of this disease. For example, the injection of the neurotoxin named hypocretin-2-saporin (HCRT2/SAP) into the lateral hypothalamus (LH) destroys the HCRT neurons, therefore diminishes the contents of HCRT in the CSF and induces narcoleptic-like behavior in rats. Transplants of various cell types have been used to induce recovery in a variety of neurodegenerative animal models. In models such as Parkinson's disease, cell survival has been shown to be small but satisfactory. Similarly, cell transplantation could be employed to implant grafts of HCRT cells into the LH or even other brain regions to treat narcolepsy. Here, we report for the first time that transplantation of HCRT neurons into the LH of HCRT2/SAP-lesioned rats diminishes narcoleptic-like sleep behavior. Therefore, cell transplantation may provide an effective method to treat narcolepsy.
... These findings are generally in line with what is known about eCB signaling and sleep (see (Prospero-Garcia et al (2016)) for in depth review on the topic). Several reports have suggested that AEA signaling may be involved in sleep induction (Mechoulam et al, 1997;Murillo-Rodriguez et al, 2003;Murillo-Rodriguez et al, 2001). Similarly, augmentation of eCB signaling alters sleep architecture to promote time spent in NREM sleep and less time in wakefulness (Huitron-Resendiz et al, 2004;Pava et al, 2014Pava et al, , 2016. ...
Article
Exposure to stress is an undeniable, but in most cases surmountable, part of life. However, in certain individuals, exposure to severe or cumulative stressors can lead to an array of pathological conditions including posttraumatic stress disorder (PTSD), characterized by debilitating trauma-related intrusive thoughts, avoidance behaviors, hyperarousal, as well as depressed mood and anxiety. In the context of the rapidly changing political and legal landscape surrounding use of cannabis products in the United States, there has been a surge of public and research interest in the role of cannabinoids in the regulation of stress-related biological processes and in their potential therapeutic application for stress-related psychopathology. Here we review the current state of knowledge regarding the effects of cannabis and cannabinoids in PTSD and the preclinical and clinical literature on the effects of cannabinoids and endogenous cannabinoid signaling systems in the regulation of biological processes related to the pathogenesis of PTSD. Potential therapeutic implications of the reviewed literature are also discussed. Lastly, we propose that a state of endocannabinoid deficiency could represent a stress-susceptibility endophenotype predisposing to the development of trauma-related psychopathology and provide biologically plausible support for the self-medication hypotheses used to explain high rates of cannabis use in patients with trauma-related disorders.
... [1][2][3] Cannabis alters the sleep-wake cycle, increases the production of melatonin, and can inhibit the arousal system by activating cannabinoid type 1 (CB 1 ) receptors in the basal forebrain and other wakepromoting centers. [9][10][11][12] Investigations have shown that the major psychoactive compound in cannabis, ∆ 9 -tetrahydrocannabinol (THC), can decrease sleep onset latency in naïve users or at low doses in experienced users (eg, 70 mg/day); however, higher doses in experienced users increased sleep latency and wake after sleep onset. 9,13,14 Indeed, frequent cannabis users (≥5 uses/week for 3 months and lifetime use ≥2 years) are reported to have shorter total sleep duration, less slow wave sleep, worse sleep efficiency, and longer sleep onset compared to controls. ...
Article
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Nicole P Bowles, Maya X Herzig, Steven A Shea Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USAThe recent legalization of cannabis for medical and recreational use in many states in the United States and internationally4,5 has resulted in a decrease in stigma and of perceived risk of cannabis use, more frequent use of cannabis, use of higher potency cannabis products, and increased dependence on cannabis use.6–8 Cannabis sativa and its derivatives are often used for improved sleep and relaxation; characteristics originally attributed to Indian hemp in the nineteenth century.1–3 Cannabis alters the sleep–wake cycle, increases the production of melatonin, and can inhibit the arousal system by activating cannabinoid type 1 (CB1) receptors in the basal forebrain and other wakepromoting centers.9–12 Investigations have shown that the major psychoactive compound in cannabis, Δ9-tetrahydrocannabinol (THC), can decrease sleep onset latency in naïve users or at low doses in experienced users (eg, 70 mg/day); however, higher doses in experienced users increased sleep latency and wake after sleep onset.9,13,14 Indeed, frequent cannabis users (≥5 uses/week for 3 months and lifetime use ≥2 years) are reported to have shorter total sleep duration, less slow wave sleep, worse sleep efficiency, and longer sleep onset compared to controls.15 The contrasting benefits of THC exposure may represent the biphasic influence of THC on CB1 receptors whereby acute use causes more activation of CB1 receptors and tendency toward sleep, but long-term use results in desensitization of the CB1 receptor and decreased downstream signaling.
... This happens in several conditions, including hypoxia, hypoglycemia and high frequency stimulation/seizures. It has also been found that adenosine extracellular concentration varies during physiological processes, where it represents a brain fatigue factor (Porkka-Heiskanen et al., 1997), thus, playing a role in sleep-wake cycle (reviewed in Murillo-Rodriguez et al., 2003;Porkka-Heiskanen and Kalinchuk, 2011;Chen, 2014;Huang et al., 2014), and cerebral blood flow (Gordon et al., 2008;McClure et al., 2011). ...
Article
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Alzheimer’s disease (AD) is the most common neurodegenerative disorder in elderly people. AD is characterized by a progressive cognitive decline and it is neuropathologically defined by two hallmarks: extracellular deposits of aggregated β-amyloid (Aβ) peptides and intraneuronal fibrillar aggregates of hyper- and abnormally phosphorylated Tau proteins. AD results from multiple genetic and environmental risk factors. Epidemiological studies reported beneficial effects of caffeine, a non-selective adenosine receptors antagonist. In the present review, we discuss the impact of caffeine and of adenosinergic system modulation on AD, in terms of pathology and therapeutics.
... For example, alertness is modulated by glutamate, monoamines, ACh, HCRT [7, 17, 31, 68-83] whereas sleep is under control of GABA [84][85][86][87][88][89][90]. The complexity of nature of sleep-modulating molecules include cytokines, hormones, purines and lipids, just to mention a few [91][92][93][94][95][96][97][98][99][100][101]. ...
Article
Background: There is a general consensus that sleep-wake cycle is controlled by neuroanatomical, neurochemical and molecular systems as well as by homeostatic and circadian complex networks. The research has shown that a molecular element that could be displaying a relevant role in the modulation of sleep is the peroxisome proliferator-activated receptor alpha (PPARα), which belongs to the family of nuclear receptor ligand-activated transcription factors that includes PPARβ/δ and PPARγ. A growing body of evidence supports the notion that PPARα is activated by natural ligands such as the anorexic lipid mediator oleoylethanolamide (OEA) or synthetic compounds including Wy14643 whereas antagonists like MK-886 block the neurobiological outcomes of PPARα. More recently, studies have reported the permissive role of PPARα by modulating diverse neurobiological functions such as inflammation, metabolic disorders, learning, degenerative diseases and sleep. Remarkably, this nuclear receptor has been described in sleep-related brain regions leading to the hypothesis that PPARα might be involved in sleep modulation inasmuch as activation of this protein promotes a robust enhancement of wakefulness while reduces sleep. Objective: In this mini review, the emerging evidence of the putative role of PPARα in sleep control is highlighted. Even though the data are derived from new areas of research, there are many reasons to believe that understanding and appreciation of PPARα functions may provide knowledge of possible mechanisms of action activated by this nuclear receptor in sleep modulation. Conclusion: Novel insights of therapeutic intervention for sleep disorders might be visualized targeting the function of PPARα in sleep abnormalities.
... The few studies assessing the ECS and sleep revealed that exogenous cannabinoids promote sleep, increase rapid eye movement (REM) sleep and the stability of non-REM (NREM) sleep, although the precise underlying pathophysiological mechanisms remain unclear (Murillo-Rodriguez 2008;Murillo-Rodriguez et al. 2003;Pava et al. 2016). ...
Article
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Although open-label observations report a positive effect of cannabinoids on non-motor symptoms (NMS) in Parkinson’s disease (PD) patients, these effects remain to be investigated in a controlled trial for a broader use in NMS in PD patients. Therefore, we decided to design a proof-of-concept study to assess the synthetic cannabinoid nabilone for the treatment of NMS. We hypothesize that nabilone will improve NMS in patients with PD and have a favorable safety profile. The NMS-Nab Study is as a mono-centric phase II, randomized, placebo-controlled, double-blind, parallel-group, enriched enrollment withdrawal study. The primary efficacy criterion will be the change in Movement Disorders Society-Unified Parkinson’s Disease-Rating Scale Part I score between baseline (i.e. randomization) and week 4. A total of 38 patients will have 80% power to detect a probability of 0.231 that an observation in the treatment group is less than an observation in the placebo group using a Wilcoxon rank-sum test with a 0.050 two-sided significance level assuming a true difference of 2.5 points between nabilone and placebo in the primary outcome measure and a standard deviation of the change of 2.4 points. The reduction of harm through an ineffective treatment, the possibility of individualized dosing, the reduction of sample size, and the possible evaluation of the influence of the placebo effect on efficacy outcomes justify this design for a single-centered placebo-controlled investigator-initiated trial of nabilone. This study should be the basis for further evaluations of long-term efficacy and safety of the use of cannabinoids in PD patients.
... Other signaling pathways could be involved in the anti-inflammatory effects observed. For instance, CB 1 R activation has been reported to increase extracellular adenosine levels (42). Adenosine promotes resolution of inflammation in LPS-induced lung injury (43), which raises the possibility that adenosine signaling may also contribute to the anti-inflammatory effects of CB 1 R agonists. ...
Article
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Cannabis sativa and its principal components, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol, are increasingly being used to treat a variety of medical problems, including inflammatory conditions. Although studies suggest that the endocannabinoid system has immunomodulatory properties, there remains a paucity of information on the effects of cannabinoids on immunity and on outcomes of infection and injury. We investigated the effects and mechanism(s) of action of cannabinoid receptor agonists, including Δ9-THC, on inflammation and organ injury in endotoxemic mice. Administration of Δ9-THC caused a dramatic early upregulation of plasma IL-10 levels, reduced plasma IL-6 and CCL-2 levels, led to better clinical status, and attenuated organ injury in endotoxemic mice. The anti-inflammatory effects of Δ9-THC in endotoxemic mice were reversed by a cannabinoid receptor type 1 (CB1R) inverse agonist (SR141716), and by clodronate-induced myeloid-cell depletion, but not by genetic invalidation or blockade of other putative Δ9-THC receptors, including cannabinoid receptor type 2, TRPV1, GPR18, GPR55, and GPR119. Although Δ9-THC administration reduced the activation of several spleen immune cell subsets, the anti-inflammatory effects of Δ9-THC were preserved in splenectomized endotoxemic mice. Finally, using IL-10-GFP reporter mice, we showed that blood monocytic myeloid-derived suppressive cells mediate the Δ9-THC-induced early rise in circulating IL-10. These results indicate that Δ9-THC potently induces IL-10, while reducing proinflammatory cytokines, chemokines, and related organ injury in endotoxemic mice via the activation of CB1R. These data have implications for acute and chronic conditions that are driven by dysregulated inflammation, such as sepsis, and raise the possibility that CB1R-signaling may constitute a novel target for inflammatory disorders.
... 8 It is hypothesized that the action of endocannabinoids on CB1 receptors triggers the release of sleep promoting neurotransmitters such as adenosine. 9 Given that cannabis acts on the brain ECS that is involved in regulatory processes such as sleep, 3 it is critical to understand the relationship between cannabis and sleep. ...
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.
... Two cannabinoid receptors CB1 and CB2 have been identified and CB1 agonists promote sleep, while CB1 antagonists increase wake (Valentino and Volkow, 2020b). Basic research has suggested that the cannabis sedative effect occurs through release of adenosine in the basal forebrain (Murillo-Rodriguez et al., 2003). There also is evidence that cannabis is involved in the control of the circadian sleep wake rhythm. ...
Article
The majority of the literature describing the relation of sleep/alertness disturbance and substance use disorders (SUD) has focused on the disruptive effects of substances with abuse liability on sleep and alertness. Rarely have studies or literature reviews assessed or discussed how sleep/alertness disturbance affects substance use. This paper focuses on the sleep/alertness disturbance side of the relation. We argue that the relation is bi-directional and review evidence showing that sleep/alertness disturbance affects all phases of the addiction cycle, including the initiation, maintenance and relapse of SUD. We review a variety of substances across all phases of the addiction cycle and conclude sleep/alertness disturbance is a critical factor in both understanding and treating SUD.
... Further studies have shown that AEA increases the amount of adenosine in the basal forebrain (Murillo-Rodriguez et al. 2003), suggesting that adenosine may also be mediating AEA's effect, although this finding has not been replicated. ...
Chapter
The sleep-wake cycle is a complex process that includes wake (W), non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep. Each phase is regulated by specialized brain structures that, by means of different neurotransmitters, maintain the constant expression of the sleep-wake cycle. Molecules like orexin, serotonin, noradrenaline, histamine, for waking; GABA, adenosine, prostaglandins, for NREM sleep and acetylcholine and glutamate for REM sleep, among other molecules are responsible for the expression and maintenance of each phase. When the endocannabinoid system was being described for the first time, almost three decades ago, oleamide’s sleep promoting properties were highlighted. Nowadays, enough evidence has been cumulated to support the endocannabinoid system role in the sleep-wake cycle regulation. The endocannabinoids oleamide anandamide, and 2-arachidonylglycerol promote NREM and/or REM sleep via the CB1R, thereby making this system a target to treat sleep disorders, such as insomnia.
... 32 33 Increasing endogenous anandamide via FAAH inhibition normalised deficits in stage N3 sleep in cannabis-dependent men experiencing withdrawal, 34 consistent with preclinical data showing that anandamide promotes slow wave sleep, possibly through increases in extracellular adenosine concentrations. [35][36][37] This effect can be blocked by administration of the CB 1 antagonist, rimonabant. 38 Indeed, clinical trials of rimonabant have reported an increased risk of sleep disturbances, 39 suggesting a role for the CB 1 receptor in mediating sleep. ...
Article
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Introduction Insomnia is a highly prevalent and costly condition that is associated with increased health risks and healthcare utilisation. Anecdotally, cannabis use is frequently reported by consumers to promote sleep. However, there is limited research on the effects of cannabis on sleep and daytime function in people with insomnia disorder using objective measures. This proof-of-concept study will evaluate the effects of a single dose of an oral cannabis-based medicine on sleep and daytime function in participants with chronic insomnia disorder. Methods and analysis A randomised, crossover, placebo-controlled, single-dose study design will be used to test the safety and efficacy of an oral oil solution (‘ETC120’) containing 10 mg Δ ⁹ -tetrahydrocannabinol (THC) and 200 mg cannabidiol (CBD) in 20 participants diagnosed with chronic insomnia disorder. Participants aged 35–60 years will be recruited over an 18-month period commencing August 2019. Each participant will receive both the active drug and matched placebo, in a counterbalanced order, during two overnight study assessment visits, with at least a 1-week washout period between each visit. The primary outcomes are total sleep time and wake after sleep onset assessed via polysomnography. In addition, 256-channel high-density electroencephalography and source modelling using structural brain MRI will be used to comprehensively examine brain activation during sleep and wake periods on ETC120 versus placebo. Next-day cognitive function, alertness and simulated driving performance will also be investigated. Ethics and dissemination Ethics approval was received from Bellberry Human Research Ethics Committee (2018-04-284). The findings will be disseminated in a peer-reviewed open-access journal and at academic conferences. Trial registration number ANZCTRN12619000714189.
... The effect of both systemic and intra-PPTg AEA administration on sleep is blocked by pretreatment with the CB1 receptor antagonist/inverse agonist SR141716A (Murillo-Rodriguez et al., 2001). Other sleep-promoting effects of systemic AEA administration could also be driven by increases in basal forebrain adenosine (Murillo-Rodriguez et al., 2003), one of the hallmarks of normal wake-sleep transitions (Blanco-Centurion et al., 2006). Direct injection of 2-AG into the lateral hypothalamus, a brain region that contains both awake-promoting orexin neurons and sleep-promoting melanin-concentrating hormone (MCH) neurons (Yamashita and Yamanaka, 2017), has been shown to increase REM sleep, likely by increasing activity in MCH-producing neurons (Perez-Morales et al., 2013). ...
Article
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Sleep is a vital function of the nervous system that contributes to brain and bodily homeostasis, energy levels, cognitive ability, and other key functions of a variety of organisms. Dysfunctional sleep induces neural problems and is a key part of almost all human psychiatric disorders including substance abuse disorders. The hypnotic effects of cannabis have long been known and there is increasing use of phytocannabinoids and other formulations as sleep aids. Thus, it is crucial to gain a better understanding of the neurobiological basis of cannabis drug effects on sleep, as well as the role of the endogenous cannabinoid system in sleep physiology. In this review article, we summarize the current state of knowledge concerning sleep-related endogenous cannabinoid function derived from research on humans and rodent models. We also review information on acute and chronic cannabinoid drug effects on sleep in these organisms, and molecular mechanisms that may contribute to these effects. We point out the potential benefits of acute cannabinoids for sleep improvement, but also the potential sleep-disruptive effects of withdrawal following chronic cannabinoid drug use. Prescriptions for future research in this burgeoning field are also provided.
... One could also speculate on the possibility that reward modulation is passed to other less wellstudied neurotransmitter systems, such as the endocannabinoid system, during sleep. This lipid molecule signaling pathway is intricately linked to stress and sleep regulation [149,150], but also is involved in processes of metaplasticity in the hippocampus [151,152] and reward processing [153]. The role of this pathway in sleep-dependent consolidation needs to be examined. ...
Article
Sleep is essential for memory formation. Active systems consolidation maintains that memory traces that are initially stored in a transient store such as the hippocampus are gradually redistributed towards more permanent storage sites such as the cortex during sleep replay. The complementary synaptic homeostasis theory posits that weak memory traces are erased during sleep through a competitive down-selection mechanism, ensuring the brain’s capability to learn new information. We discuss evidence from neuropharmacological experiments in humans to show how major neurotransmitters and neuromodulators are implicated in these memory processes. As to the major excitatory neurotransmitter glutamate that plays a prominent role in inducing synaptic consolidation, we show that these processes, while strengthening cortical memory traces during sleep, are insufficient to explain the consolidation of hippocampus-dependent declarative memories. In the inhibitory GABAergic system, we will offer insights how drugs may alter the intricate interplay of sleep oscillations that have been identified to be crucial for strengthening memories during sleep. Regarding the dopaminergic reward system, we will show how it is engaged during sleep replay, but that dopaminergic neuromodulation likely plays a side role for enhancing relevant memories during sleep. Also, we briefly go into basic evidence on acetylcholine and cortisol whose low tone during slow wave sleep (SWS) is crucial in supporting hippocampal-to-neocortical memory transmission. Finally, we will outline how these insights can be used to improve treatment of neuropsychiatric disorders focusing mainly on anxiety disorders, depression, and addiction that are strongly related to memory processing.
... More specifically, exogenously administered CB 1 receptor agonists enhance NREM sleep in rats and humans [208,209]. The administration of CB 1 receptor antagonists increased wake time and reduced NREM sleep time in rats [210,211]. Anandamide administration in the PPT decreased wakefulness and increased SWS, and these effects were reversed by a CB 1 receptor antagonist [212]. One hypothesis is that endocannabinoids act in the pons and medulla to enhance the release of acetylcholine [207]. ...
Article
The development of alcohol use disorder (AUD) involves binge drinking to high levels of intoxication that leads to compulsive intake, the loss of control in limiting intake, and a negative emotional state when alcohol is removed. This cascade of events occurs over an extended period within a three-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These three stages map onto the dysregulation of functional domains of incentive salience/habits, negative emotional states, and executive function, mediated by the basal ganglia, extended amygdala, and frontal cortex, respectively. Sleep disturbances, alterations of sleep architecture, and the development of insomnia are ubiquitous in AUD and also map onto the three stages of the addiction cycle. During the binge/intoxication stage, alcohol intoxication leads to a faster sleep onset, but sleep quality is poor relative to nights when no alcohol is consumed. The reduction of sleep onset latency and increase in wakefulness later in the night may be related to the acute effects of alcohol on GABAergic systems that are associated with sleep regulation and the effects on brain incentive salience systems, such as dopamine. During the withdrawal/negative affect stage, there is a decrease in slow-wave sleep and some limited recovery in REM sleep when individuals with AUD stop drinking. Limited recovery of sleep disturbances is seen in AUD within the first 30 days of abstinence. The effects of withdrawal on sleep may be related to the loss of alcohol as a positive allosteric modulator of GABAA receptors, a decrease in dopamine function, and the overactivation of stress neuromodulators, including hypocretin/orexin, norepinephrine, corticotropin-releasing factor, and cytokines. During the preoccupation/anticipation stage, individuals with AUD who are abstinent long-term present persistent sleep disturbances, including a longer latency to fall asleep, more time awake during the night, a decrease in slow-wave sleep, decreases in delta electroencephalogram power and evoked delta activity, and an increase in REM sleep. Glutamatergic system dysregulation that is observed in AUD is a likely substrate for some of these persistent sleep disturbances. Sleep pathology contributes to AUD pathology, and vice versa, possibly as a feed-forward drive to an unrecognized allostatic load that drives the addiction process.
Article
The newly discovered endocannabinoid system (ECS) and the ongoing research into its role in the central nervous system (CNS) has important ramifications in the understanding and treatment of posttraumatic stress disorder (PTSD). While the connection with this system and PTSD is in its early stages, and only one small clinical study involving patients with PTSD being treated with an endocannabinoid agonist has been published to date, [1] nonetheless emerging investigations into the endocannabinoid system are promising and warrant a dialogue and speculation about the potential benefits of endocannabinoid ligands in the treatment of PTSD. This chapter will consider three areas related to the endocannabinoid system and how it may be connected to the field of posttraumatic stress disorder. First will be an overview of the recent discovery of endocannabinoid system. Next, research studies pointing to potentially interesting relationships between cannabinoids, endocannabinoids and PTSD will be discussed. Finally, clinical issues and questions arising out of actual field experience using nabilone, a synthetic cannabinoid, will be presented. This latter area will be of interest to clinicians who may consider using a synthetic cannabinoid for the first time with a PTSD patient. It will be based on the above mentioned clinical trial which used a synthetic cannabinoid in managing treatment resistant PTSD nightmares which was carried out by this author.
Chapter
Good sleep is vital for good health, and poor sleep, in particular insomnia, is associated with a range of poor health outcomes. Sleep disorders are common and a key reason why people self-medicate with cannabis. We have two key biological mechanisms which work together to regulate our sleep-wake cycle, the processes of sleep-wake homeostasis and our circadian rhythms. The endocannabinoid system is involved in the circadian sleep-wake cycle, including maintenance and promotion of sleep, and may provide the link between the circadian regulation systems and the physiological process of sleep. Cannabis has been used for centuries to treat sleep disorders. Preclinical and clinical evidence indicate that cannabidiol and tetrahydrocannabinol may have a role to play in the treatment of sleep disorders.
Article
Recent studies suggest the possible involvement of serotonergic and endocannabinoid systems in analgesic, anxiolytic, and anticonvulsant-like actions of paracetamol. Considering the fact that these systems play intricate roles in affective disorders, we investigated the effects of paracetamol in depression-like and compulsion-like behavior. Swiss mice (20-22 g) were subjected to forced swim, tail suspension, or marble-burying tests after an injection of paracetamol either alone or in the presence of AM251 (a CB1 antagonist), fenclonine (pCPA: a 5-HT synthesis inhibitor), AM404 (anandamide uptake inhibitor) or fluoxetine. Paracetamol dose dependently (50-400 mg/kg) decreased depressive and compulsive behaviors. These effects were comparable to those of fluoxetine (5, 10, or 20 mg/kg) and AM404 (10 or 20 mg/kg). Interestingly, fenclonine pretreatment completely abolished the effects of a 50 mg/kg dose of paracetamol. However, similar effects were not observed in AM251-pretreated mice at the same dose. In contrast, AM251 completely antagonized the effects of the 400 mg/kg dose, which was otherwise partially blocked in fenclonine-treated mice. Similar sets of results were observed with fluoxetine and AM404. Thus, it appears that paracetamol-induced antidepressant-like and anticompulsive effects may, at least partially, involve both the serotonergic and the endocannabinoid system. In addition, coadministration of paracetamol and fluoxetine/AM404 at subeffective doses produced synergistic effects, indicating that subthreshold doses of fluoxetine and paracetamol may enable better management in depression and obsessive-compulsive disorder comorbid patients.
Article
Context: Involvement of the endocannabinoid system (eCBs) in a wide variety of physiological and pathological processes has attracted a growing interest. In fact, identification of this ubiquitous signaling system has provided new insights into the underlying pathophysiologic mechanisms of various diseases which may lead to development of novel therapeutic strategies. Evidence Acquisitions: The limited efficacy of current pharmacological treatments for neurological disorders has led to considerable research interests in new drug development. Based on the modulatory effects of the eCBs on neuroinflammatory and neurodegenerative processes, pharmacological manipulation of the eCBs may prove beneficial in neurological problems. Results: The eCBs is involved in the survival signaling pathways, neural plasticity, and neuroprotection. Furthermore, the eCBs has proved therapeutic effects against the neurological diseases such as multiple sclerosis, epilepsy, mood and movement disorders, spinal cord injury, stroke, and Alzheimer’s disease. Conclusions: In the present manuscript, an overview on the regulatory role of the eCBs in neurological disorders underscores the importance of systematic analysis of the efficacy and mechanisms of action of cannabinoid-based drugs. Based on the antineuroinflammatory and anti-neurodegenerative effects of cannabinoids, the development of drugs without psychoactive effects would be a promising therapeutic alternative for neurological diseases.
Chapter
During the last 10 years, two of the major discoveries made on the control of waking and sleep that have helped revolutionize our understanding of these two states will be addressed in regard to their relevance to RBD and its subtypes. This research was directed at the partly cholinergic pedunculopontine nucleus (PPN), the portion of the reticular activating system (RAS) that is active during waking and REM sleep, but less active during slow-wave sleep, and at its REM sleep-related target, the subcoeruleus nucleus dorsalis (SubCD). As such, the PPN modulates the manifestation of waking through ascending projections to the intralaminar thalamus, as well as the manifestation of REM sleep through descending projections to the SubCD. It was found that these regions possess a proportion of cells that are electrically coupled through gap junctions, thus promoting coherence within each nucleus, and that every cell in the PPN manifests gamma-band activity through intrinsic membrane properties that can be exported to its targets. Neither mechanism has been studied extensively for its involvement in RBD or its subtypes. However, there is little doubt that research into these areas will permit a deeper understanding of RBD disease subtypes and their underlying mechanisms and point to novel directions for treatment.
Research
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¡Todo mundo duerme! El sueño es tan familiar para cada uno de nosotros y, aún así, es un fenómeno envuelto en el misterio de sus funciones. Con tremendos y significativos avances como el descubrimiento del electroencefalograma en 1929, de la descripción del sueño de movimientos oculares rápidos en 1953, de la descripción de la existencia del reloj endógeno circadiano en 1972, de la localización del sitio relacionado con la disfunción del sueño en el caso del síndrome de la apnea obstructiva en 1965, del tratamiento no invasivo denominado CPAP (por sus siglas en ingles: Continuous Positive Airway Pressure) para el síndrome de la apnea del sueño en 1981 y del descubrimiento del gen relacionado con ritmos denominado CLOCK en la mosca de la fruta Drosophila en 1990, todavía continuamos preguntándonos ¿qué es el sueño? ¿Para qué dormimos? Es gratificante observar cómo la medicina del sueño va ganando espacios en la sociedad y se le otorga la importancia que merece, en especial cuando se relaciona con trastornos del dormir. Dicho interés se debe al creciente número de artículos vinculados con el tema del sueño los cuales han sido publicados en diferentes medios de comunicación, tanto de divulgación científica como de difusión social. El presente trabajo es el resultado del esfuerzo conjunto de científicos expertos en el área del estudio del ciclo sueño-vigilia que han contribuido con conocimientos actuales y avanzados relacionados con el tema. El propósito del libro es favorecer la comprensión sobre aspectos básicos y clínicos del sueño con una aproximación adecuada. Espero que el presente trabajo tenga una gran aceptación entre estudiantes, profesores e investigadores y cumpla con las expectativas de todo lector.
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Chronic diseases are due to deviations of fundamental physiological systems, with different pathologies being characterised by similar malfunctioning biological networks. The ensuing compensatory mechanisms may weaken the body's dynamic ability to respond to further insults and reduce the efficacy of conventional single target treatments. The multitarget, systemic, and prohomeostatic actions emerging for plant cannabinoids exemplify what might be needed for future medicines. Indeed, two combined cannabis extracts were approved as a single medicine (Sativex(®)), while pure cannabidiol, a multitarget cannabinoid, is emerging as a treatment for paediatric drug-resistant epilepsy. Using emerging cannabinoid medicines as an example, we revisit the concept of polypharmacology and describe a new empirical model, the 'therapeutic handshake', to predict efficacy/safety of compound combinations of either natural or synthetic origin.
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The wiring diagram of the main nuclei of the reticular activating system (RAS) is well known, as are the intrinsic membrane properties of cells in these nuclei. The major transmitter inputs to these cells have also been described, as have the main cell types and their transmitter outputs. In addition, the presence of electrical coupling in some cells in these nuclei has been determined. These properties allow us to gain a measure of the types of firing patterns that these neurons are capable of maintaining. The firing patterns and transmitter inputs of these cells across the wake-sleep cycle have also been determined. Current research is directed at how the cell clusters within the RAS nuclei function to modulate thalamic and cortical EEG rhythms in the presence of sporadic and continuous sensory inputs. This information is critical for determining how the states of waking and REM sleep are modulated by the RAS.
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Sleep apnea affects 2-4 % of the population. It is characterised by repetitive episodes of brief upper airway obstruction during sleep, with associated arousal from sleep. Consequences of untreated sleep apnea include excessive daytime sleepiness and impaired cognitive functioning and driving performance. Sleep apnea is also associated with a number of co-morbidities, including hypertension, insomnia and cardiovascular disease. As such, many sleep apnea patients are on medications that can potentially affect their sleep apnea severity and daytime functioning, including driving performance. Centrally-acting depressant drugs, including alcohol, antihypertensives, narcotics and sedatives, can cause respiratory depression and worsen sleep apnea. They may increase sleepiness and further impair driving performance either through direct actions on the central nervous system or through increasing sleep apnea severity. This chapter describes the effects of sleep apnea on daytime sleepiness, cognitive functioning and driving performance, as well as the drugs affecting waking and nocturnal respiration.
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The newly discovered endocannabinoid system (ECS) and the ongoing research into its role in the central nervous system (CNS) has important ramifications in the understanding and treatment of posttraumatic stress disorder (PTSD). While the connection with this system and PTSD is in its early stages, and only one small clinical study involving patients with PTSD being treated with an endocannabinoid agonist has been published to date, [1] nonetheless emerging investigations into the endocannabinoid system are promising and warrant a dialogue and speculation about the potential benefits of endocannabinoid ligands in the treatment of PTSD. This chapter will consider three areas related to the endocannabinoid system and how it may be connected to the field of posttraumatic stress disorder. First will be an overview of the recent discovery of endocannabinoid system. Next, research studies pointing to potentially interesting relationships between cannabinoids, endocannabinoids and PTSD will be discussed. Finally, clinical issues and questions arising out of actual field experience using nabilone, a synthetic cannabinoid, will be presented. This latter area will be of interest to clinicians who may consider using a synthetic cannabinoid for the first time with a PTSD patient. It will be based on the above mentioned clinical trial which used a synthetic cannabinoid in managing treatment resistant PTSD nightmares which was carried out by this author.
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Cannabis and, to a lesser extent, synthetic cannabinoids are used during adolescence, a period in which multiple brain areas are still undergoing development. Among such areas is the hypothalamus, which is implicated in the control of sleep-wake cycle. In the present report, we show that exposing adolescent rats to the cannabinoid receptor agonist WIN 55, 212-2 (0.1, 0.3 or 1.0 mg/kg, i.p) for 14 days during adolescence (i.e., from post-natal day 30-44) resulted in significant sleep disturbances when the animals became adult (post-natal day 80). These included decreased wakefulness and enhanced rapid eye movement sleep. Furthermore, we found that labeling for NeuN, a marker of postmitotic neurons, was significantly increased the dorsomedial hypothalamic nucleus of rats treated with WIN 55, 212-2. The results suggest that excessive cannabinoid receptor activation during adolescence can persistently influence sleep patterns and neuronal activity later in life.
Chapter
Despite the fact that medical properties of Cannabis have been recognized for more than 5000 years, the use of Cannabis for medical purposes have recently reemerged and became more accessible. Cannabis is usually employed as a self-medication for the treatment of insomnia disorder. However, the effects of Cannabis on sleep depend on multiple factors such as metabolomic composition of the plant, dosage and route of administration. In the present chapter, we reviewed the main effect Cannabis on sleep. We focused on the effect of “crude or whole plant” Cannabis consumption (i.e., smoked, oral or vaporized) both in humans and experimental animal models.
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Appendix S1. Study characteristics of papers reporting baseline adenosine concentrations. Appendix S2. Study characteristics of papers and abstracts not reporting absolute baseline adenosine concentrations or only reporting them in low‐resolution figures. Appendix S3. Adenosine monophosphate concentrations and corresponding study characteristics.
Chapter
Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the primary active component in Cannabis sativa preparations such as hashish and marijuana, signals by binding to cell surface receptors. Two types of receptors have been cloned and characterized as cannabinoid (CB) receptors. CB1 receptors (CB1R) are ubiquitously present in the central nervous system (CNS) and are present in both inhibitory interneurons and excitatory neurons at the presynaptic terminal. CB2 receptors (CB2R) are demonstrated in microglial cells, astrocytes, and several neuron subpopulations and are present in both pre- and postsynaptic terminals. The majority of studies on these receptors have been conducted in the past two and half decades after the identification of the molecular constituents of the endocannabinoid (eCB) system that started with the characterization of CB1R. Subsequently, the seminal discovery was made, which suggested that alcohol (ethanol) alters the eCB system, thus establishing the contribution of the eCB system in the motivation to consume ethanol. Several preclinical studies have provided evidence that CB1R significantly contributes to the motivational and reinforcing properties of ethanol and that the chronic consumption of ethanol alters eCB transmitters and CB1R expression in the brain nuclei associated with addiction pathways. Additionally, recent seminal studies have further established the role of the eCB system in the development of ethanol-induced developmental disorders, such as fetal alcohol spectrum disorders (FASD). These results are augmented by in vitro and ex vivo studies, showing that acute and chronic treatment with ethanol produces physiologically relevant alterations in the function of the eCB system during development and in the adult stage. This chapter provides a current and comprehensive review of the literature concerning the role of the eCB system in alcohol abuse disorders (AUD).
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The endocannabinoid system comprises receptors (CB1 and CB2 cannabinoid receptors), enzymes (Fatty Acid Amide Hydrolase [FAAH], which synthesizes the endocannabinoid anandamide), as well as the anandamide membrane transporter (AMT). Importantly, previous experiments have demonstrated that the endocannabinoid system modulates multiple neurobiological functions, including sleep. For instance, SR141716A (the CB1 cannabinoid receptor antagonist) as well as URB597 (the FAAH inhibitor) increase waking in rats whereas VDM-11 (the blocker of the AMT) enhances sleep in rodents. However, no further evidence is available regarding the neurobiological role of the endocannabinoid system in the homeostatic control of sleep. Therefore, the aim of the current experiment was to test if SR141716A, URB597 or VDM-11 would modulate the sleep rebound after sleep deprivation. Thus, these compounds were systemically injected (5, 10, 20mg/Kg; ip; separately each one) to rats after prolonged waking. We found that SR141716A and URB597 blocked in dose-dependent fashion the sleep rebound whereas animals treated with VDM-11 displayed sleep rebound during the recovery period. Complementary, injection after sleep deprivation of either SR141716A or URB597 enhanced dose-dependently the extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, as well as adenosine while VDM-11 caused a decline in contents of these molecules. These findings suggest that SR141716A or URB597 behave as a potent stimulants since they suppressed the sleep recovery period after prolonged waking. It can be concluded that elements of the endocannabinoid system, such as the CB1 cannabinoid receptor, FAAH and AMT, modulate the sleep homeostasis after prolonged waking.
Article
Cannabinoids, including the two main phytocannabinoids Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), are being increasingly utilised as pharmacological interventions for sleep disorders. THC and CBD are known to interact with the endocannabinoid and other neurochemical systems to influence anxiety, mood, autonomic function, and circadian sleep/wake cycle. However, their therapeutic efficacy and safety as treatments for sleep disorders are unclear. The current systematic review assessed the available evidence base using PubMed, Scopus, Web of Science, Embase, CINAHL and PsycInfo databases. A total of 14 preclinical studies and 12 clinical studies met inclusion criteria. Results indicated that there is insufficient evidence to support routine clinical use of cannabinoid therapies for the treatment of any sleep disorder given the lack of published research and the moderate-to-high risk of bias identified within the majority of preclinical and clinical studies completed to-date. Promising preliminary evidence provide the rationale for future randomised controlled trials of cannabinoid therapies in individuals with sleep apnea, insomnia, post-traumatic stress disorder-related nightmares, restless legs syndrome, rapid eye movement sleep behaviour disorder, and narcolepsy. There is a clear need for further investigations on the safety and efficacy of cannabinoid therapies for treating sleep disorders using larger, rigorously controlled, longer-term trials.
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Cannabidiol (CBD) is an abundant non-psychoactive phytocannabinoid in Cannabis extracts which has high affinity on a series of receptors, including type 1 cannabinoid receptor (CB1), type 2 cannabinoid receptor (CB2), GPR55, transient receptor potential vanilloid (TRPV), and peroxisome proliferator-activated receptor gamma (PPARγ). By modulating the activities of these receptors, CBD exhibits multiple therapeutic effects, including neuroprotective, antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, analgesic and anti-cancer properties. CBD could also be applied to treat or prevent COVID-19 and its complications. Here, we provide a narrative review of CBD's applications in human diseases: from mechanism of action to clinical trials.
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Cannabis sativa has long been used for medicinal purposes. To improve safety and efficacy, compounds from C. sativa were purified or synthesized and named under an umbrella group as cannabinoids. Currently, several cannabinoids may be prescribed in Canada for a variety of indications such as nausea and pain. More recently, an increasing number of reports suggest other salutary effects associated with endogenous cannabinoid signaling including cardioprotection. The therapeutic potential of cannabinoids is therefore extended; however, evidence is limited and mechanisms remain unclear. In addition, the use of cannabinoids clinically has been hindered due to pronounced psychoactive side effects. This review provides an overview on the endocannabinoid system, including known physiological roles, and conditions in which cannabinoid receptor signaling has been implicated.
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Acupuncture and its modified forms have been used to treat multiple medical conditions, but whether the diverse effects of acupuncture are intrinsically linked at the cellular and molecular level and how they might be connected have yet to be determined. Recently, an emerging role for the endocannabinoid system (ECS) in the regulation of a variety of physiological/pathological conditions has been identified. Overlap between the biological and therapeutic effects induced by ECS activation and acupuncture has facilitated investigations into the participation of ECS in the acupuncture-induced beneficial effects, which have shed light on the idea that the ECS may be a primary mediator and regulatory factor of acupuncture’s beneficial effects. This review seeks to provide a comprehensive summary of the existing literature concerning the role of endocannabinoid signaling in the various effects of acupuncture, and suggests a novel notion that acupuncture may restore homeostasis under different pathological conditions by regulating similar networks of signaling pathways, resulting in the activation of different reaction cascades in specific tissues in response to pathological insults.
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This study examined the prevalence of illegal drug use in UK students and motivators behind such behaviour. Additionally, we explored possible relationships between substance use, psychosocial motivators, and psychiatric distress. N=543 students completed online measures of substance use, anxiety, depression, perceived stress, insomnia. A series of reasons behind their use were ranked based on importance. Reported cannabis, cocaine, nitrous oxide, ketamine and MDMA use were most prevalent based on lifetime, past year, and month assessments. The experience of anxiety, depression, perceived stress, and insomnia were related to increased reports of substance use. Poor self-confidence and self-medication were key motivators of illicit drug use in those presenting greater psychiatric distress. These outcomes add to the sparse body of literature concerning illicit substance use in relation to psychiatric distress amongst UK students. Furthermore, we provided novel insight into the psychosocial motivators of such use.
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Marijuana extract, given in daily doses containing 70 to 210 mg delta-9-tetrahydrocannabinol (THC), induced effects on sleep that were virtually identical to those produced by the same doses of relatively pure (96%) THC. Both drugs reduced eye movements density with some tolerance developing to this effect. Stage 4 tendend to increase with drug administration. Abrupt withdrawal led to extremely high densities of eye movement, increased rapid eye movement (REM) durations, and a sharp but transient fall in stage 4 to baseline levels. These effects may be useful in the elucidation of the pharmacology of sleep. The effects on sleep of THC administration (but not withdrawal) closely resemble those induced by lithium. For this reason, we suggest further studies of THC in affective disorders. Evidence available thus far suggests that THC produces dysphoric symptoms in unipolar but not in bipolar depressed patients; these differences in response may prove of diagnostic value. An adequate therapeutic trial of THC in bipolar depressed patients has not yet been carried out.
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Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
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Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
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[3H]CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of [3H]CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.
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A series of experiments was conducted to determine the effects of orally administered 1-trans-Δ-9-tetrahydrocannabinol (THC) on both undisturbed and experimentally altered (by rapid eye movement [REM] deprivation) sleep patterns of young adult male volunteers. In the deprivation experiments, the effects of a semisynthetic Δ-6a-10-THC homologue, synhexl, were also studied. In the normative studies, 4 subjects received THC in doses ranging from 61 to 258 μg per kilogram shortly before sleep onset, while in the deprivation experiments 2 subjects received either THC (244 μg per kilogram and 259 μg per kilogram) or synhexl (733 μg per kilogram and 777 μg per kilogram) the morning after the second of 2 consecutive nights of REM deprivation. In both normative and deprivation experiments, all-night sleep recordings were taken during base-line, drug, and postdrug conditions. The results of both types of experiments were consistent in demonstrating increments in Stage 4 sleep and decrements in REM sleep. In the normative experiments, reduction in Stage 1 and time awake after sleep onset were observed at the highest dose level. Interpretation of these results and their relation to the effects of other psychoactive compounds upon sleep pattern are discussed.
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Activation of cannabinoid receptors inhibits voltage-gated Ca2+ channels and activates K+ channels, reminiscent of other G-protein-coupled signaling pathways that produce presynaptic inhibition. We tested cannabinoid receptor agonists for effects on excitatory neurotransmission between cultured rat hippocampal neurons. Reducing the extracellular Mg2+ concentration to 0.1 mM elicited repetitive, transient increases in intracellular Ca2+ concentration ([Ca2+]i spikes) that resulted from bursts of action potentials, as measured by combined whole-cell current clamp and indo-1-based microfluorimetry. Pharmacological characterization indicated that the [Ca2+]i spikes required glutamatergic synaptic transmission. Cannabinoid receptor ligands inhibited stereoselectively the frequency of [Ca2+]i spiking in the rank order of potency: CP 54,939 > CP 55,940 > Win 55,212-2 > anandamide, with EC50 values of 0.36, 1.2, 2.7, and 71 nM, respectively. CP 55,940 was potent, but not efficacious, and reversed the inhibition produced by Win 55,212-2, indicating that it is a partial agonist. Inhibition of [Ca2+]i spiking by Win 55,212-2 was prevented by treatment of cultures with active, but not heat-treated, pertussis toxin. Win 55,212-2 (100 nM) inhibited stereoselectively CNQX-sensitive excitatory postsynaptic currents (EPSCs) elicited by presynaptic stimulation with an extracellular electrode, but did not affect the presynaptic action potential or currents elicited by direct application of kainate. Consistent with a presynaptic site of action, Win 55,212-2 increased both the number of response failures and the coefficient of variation of the evoked EPSCs. In contrast, cannabimimetics did not affect bicuculline-sensitive inhibitory postsynaptic currents. Thus, activation of cannabinoid receptors inhibits the presynaptic release of glutamate via an inhibitory G-protein.
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Both subjective and electroencephalographic arousal diminish as a function of the duration of prior wakefulness. Data reported here suggest that the major criteria for a neural sleep factor mediating the somnogenic effects of prolonged wakefulness are satisfied by adenosine, a neuromodulator whose extracellular concentration increases with brain metabolism and which, in vitro, inhibits basal forebrain cholinergic neurons. In vivo microdialysis measurements in freely behaving cats showed that adenosine extracellular concentrations in the basal forebrain cholinergic region increased during spontaneous wakefulness as contrasted with slow wave sleep; exhibited progressive increases during sustained, prolonged wakefulness; and declined slowly during recovery sleep. Furthermore, the sleep-wakefulness profile occurring after prolonged wakefulness was mimicked by increased extracellular adenosine induced by microdialysis perfusion of an adenosine transport inhibitor in the cholinergic basal forebrain but not by perfusion in a control noncholinergic region.
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We tested the hypothesis that N-[(1S, trans)-2-hydroxycyclopentyl]adenosine (GR79236), a novel adenosine A1 receptor agonist, would suppress sleep-related apnea in the rat at doses not associated with hypotension or hypothermia. Nine adult Sprague-Dawley rats were instrumented for chronic recording of sleep by electroencephalographic and electromyographic monitoring. Respirations were measured by single chamber plethysmograph, and blood pressure and heart period were transduced by a telemetric implant. Each rat was polygraphically recorded for 6 hours on four occasions in random order, with recordings for an individual animal separated by at least 3 days. Fifteen minutes prior to each recording (0945 hours) each animal received a 1 ml/kg intraperitoneal bolus injection of one of four injectates: saline (control) or 0.03 mg/kg, 0.3 mg/kg, or 3 mg/kg of GR79236. The study was a repeated-measures balanced design such that each animal was recorded exactly once for each injectate. The rate of spontaneous apneas (pauses > 2.5 seconds) was significantly reduced during all sleep stages by all doses of GR79236. At the highest dose, apnea index was reduced by over 70% in both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. In contrast, GR79236 had no effect on sleep stage volumes or blood pressure at any dose tested. Heart rate and core temperature were reduced only at the highest dose (3 mg/kg). We conclude that the adenosine A1 receptor agonist GR79236 significantly suppresses apnea expression in all sleep stages at doses not associated with significant changes in sleep architecture, blood pressure, heart rate, or core temperature.
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Central cannabinoid systems have been implicated in appetite regulation by the respective hyperphagic actions of exogenous cannabinoids, such as delta9-THC, and hypophagic effects of selective cannabinoid receptor antagonists. This study examined whether an endogenous cannabinoid, anandamide, could induce overeating, via a specific action at central (CB1) cannabinoid receptors. Pre-satiated male rats (n=18), received subcutaneous injections of anandamide (0.5, 1.0, 5.0, 10.0 mg/kg) before 3-h, nocturnal food intake tests. In a second series of intake tests (n=8), anandamide injection (1.0 mg/kg) was preceded by injection of the specific CB1 receptor antagonist, SR141716 (0.1, 0.5, 1.0 mg/kg SC). All doses of anandamide induced significant overeating, with 1.0 mg/kg being most potent. Additionally, hyperphagia induced by 1.0 mg/kg anandamide was dose-dependently attenuated by SR141716 pretreatment. This first demonstration of anandamide-induced, CB -mediated, overeating provides important evidence for the involvement of a central cannabinoid system in the normal control of eating.
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This investigation reports the possible role of the endocannabinoid anandamide in modulating appetitive behaviour. Given that cannabinoids have been used clinically to stimulate appetite in HIV and cancer chemotherapy patients, there has been a renewed interest in the involvement of cannabinoids in appetite modulation. This is the first report on the administration of anandamide into the ventromedial hypothalamus. Pre-satiated rats received an intrahypothalamic injection of anandamide (50 ng 0.5 μl−1) followed by measurement of food intake at 3 h post injection. Administration of anandamide induced significant hyperphagia. Pretreatment with the selective CB1 cannabinoid antagonist SR 141716 (30 μg 0.5 μl−1), 30 min prior to anandamide injection resulted in an attenuation of the anandamide-induced hyperphagia (P<0.001). This study demonstrates that intrahypothalamic anandamide initiates appetite by stimulation of CB1 receptors, thus providing evidence on the involvement of hypothalamic endocannabinoids in appetite initiation. British Journal of Pharmacology (2001) 134, 1151–1154; doi:10.1038/sj.bjp.0704379
Article
Both subjective and electroencephalographic arousal diminish as a function of the duration of prior wakefulness. Data reported here suggest that the major criteria for a neural sleep factor mediating the somnogenic effects of prolonged wakefulness are satisfied by adenosine, a neuromodulator whose extracellular concentration increases with brain metabolism and which, in vitro, inhibits basal forebrain cholinergic neurons. In vivo microdialysis measurements in freely behaving cats showed that adenosine extracellular concentrations in the basal forebrain cholinergic region increased during spontaneous wakefulness as contrasted with slow wave sleep; exhibited progressive increases during sustained, prolonged wakefulness; and declined slowly during recovery sleep. Furthermore, the sleep-wakefulness profile occurring after prolonged wakefulness was mimicked by increased extracellular adenosine induced by microdialysis perfusion of an adenosine transport inhibitor in the cholinergic basal forebrain but not by perfusion in a control noncholinergic region.
Article
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.
Article
Anandamide and allied fatty acylethanolamides (AEs) may act as signalling molecules in brain and peripheral tissues. In the present study, we describe an electron-impact gas chromatography/mass spectrometry (GC/MS) method based on isotope dilution, which may be used for the identification and quantification of anandamide and other AEs in biological matrices. The calibration curves for standard AEs were linear over the range 0–1000 pmol (r2=0.99) with a coefficient of variation of 4% at 2.5 pmol. Detection and quantification limits were in the high fmol to low pmol range for all AEs. Using this method we measured nanomolar concentrations of three endogenous AEs in deproteinated rat blood plasma (anandamide: 5.2 pmol/ml; palmitylethanolamide: 16.7 pmol/ml; oleylethanolamide: 8.1 pmol/ml). These results are consistent with a regulatory role of anandamide and other AEs in peripheral tissues.
Article
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.
Article
The background knowledge leading to the isolation and identification of anandamide and 2-arachidonoyl glycerol, the principal endocannabinoids is described. The structure–activity relationships of these lipid derivatives are summarized. Selected biochemical and pharmacological topics in this field are discussed, the main ones being levels of endocannabinoids in unstimulated tissue and cells, biosynthesis, release and inactivation of endocannabinoids, the effects of `entourage' compounds on the activities of anandamide and 2-arachidonoyl glycerol, their signaling mechanisms and effects in animals.
Article
This investigation reports the possible role of the endocannabinoid anandamide on modulating the behavioral and neurochemical consequences of semi-starvation. We studied the effect of very low dose anandamide (0.001 mg/kg) administration on food intake, cognitive function and catecholaminergic and serotonergic pathways in two murine brain areas concerned with appetite (hypothalamus) and learning (hippocampus), and the peripheral corticosterone response to the stress of 40% diet restriction. Anandamide-treated mice consumed 44% more food (P<0.05) during 1 week of 2.5-h feeding each day. In the hypothalamus, there were significantly increased concentrations of norepinephrine (P<0.01), dopamine (P<0.05) and 5-hydroxytryptamine (5-HT) (P<0.001). In the hippocampus, anandamide increased significantly norepinephrine and dopamine, but decreased 5-HT (all at P<0.001). Diet restriction was accompanied in both areas by a significant decrease in all neurotransmitter concentrations that were partially restored by anandamide for dopamine and 5-HT, but not for norepinephrine. In animals on diet restriction, anandamide significantly improved impaired maze performance. Norepinephrine turnover and plasma corticosterone levels were also raised significantly by anandamide. The fact that low dose anandamide improved food intake, cognitive function and reversed some of the neurotransmitter changes caused by diet restriction, might have implications for the treatment of cachexia associated with acquired immunodeficiency syndrome (AIDS) and cancer, for mood changes sometimes associated with dieting, and in the extreme case, of patients with anorexia.
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
The neuronal distribution of cannabinoid receptor in the adult rat brain is reported, combining receptor binding radioautography using the synthetic psychoactive cannabinoid ligand CP55,940 with in situ hybridization histochemistry using oligonucleotide probes complementary to rat cannabinoid receptor cDNA. In the cerebral cortex, especially in the frontal and cingulate cortex, dense binding was found in layers I and VI together with slight mRNA levels in a majority of both pyramidal and non-pyramidal-shaped neurons and of high mRNA levels in a moderate number of non-pyramidal-shaped neurons especially in layers II-III and V-VI. In the hippocampal dentate gyrus, very dense staining was found in the molecular layer together with high mRNA levels in a moderate number of hilar neurons close to the granular layer. In Ammon's horn, especially in the CA3 sector, very dense binding was found in the dendritic layers together with slight mRNA levels in the majority of the pyramidal cells and high mRNA levels in a moderate number of interneurons. In the basal ganglia, binding was very dense in the lateral putamen, substantia nigra pars reticulata, globus pallidus and entopeduncular nucleus, moderate in the medial putamen and caudate; and slight in the accumbens, together with slight to moderate mRNA levels in the striatal medium-sized neurons. Together with slight binding, slight to moderate mRNA levels were found in the majority of the neurons in the subthalamic nucleus. No binding and mRNA were found in the substantia nigra pars compacta and ventral tegmental area. Slight to moderate binding was found together with slight to moderate mRNA levels in the majority of neurons in the anterior olfactory nucleus; septum, especially medial septum and diagonal band of Broca; amygdala, especially basolateral amygdala; lateral habenula; ventromedial hypothalamic nucleus; lateral interpeduncular nucleus; central gray, dorsal cochlear nucleus; parabrachial nucleus; dorsal pontine tegmentum; pontine nuclei; commissural part of the nucleus tractus solitarius; inferior olive and dorsal horn of the spinal cord. In the cerebellum, very dense binding was found in the molecular layer together with slight mRNA levels in the majority of the granule cells and moderate mRNA levels in the basket and stellate cells. In conclusion, this study provides, for the first time, indirect assessment of the neurons containing cannabinoid receptor in the entire adult rat brain and will serve as a basis for future direct morphological confirmation using receptor immunohistochemistry and for functional studies.
Article
We have examined the effects on sleep and brain temperature of bilateral microinjections of adenosine and adenosine analogs to the preoptic area (PO) of rats. Administration of adenosine (12.5 nmoles), a nonselective adenosine A1/A2 receptor agonist NECA (N-ethyl-carboxamido-adenosine, 1.0 nmole), and the selective adenosine A1 receptor agonist CPA (cyclopentyladenosine, 0.25, 0.5 nmoles) increased total sleep primarily through an enhancement in deep slow-wave sleep (SWS2), while adenosine also increased REM sleep. Administration of 12.5 nmoles adenosine and 0.25 nmoles CPA did not affect brain temperature, while 1.0 nmole NECA and 0.5 nmoles CPA caused a transient and prolonged hypothermia, respectively. Administration of the selective adenosine A2 receptor agonist CV-1808 (2-phenylaminoadenosine, 5, 10 nmoles) had no effect on sleep or brain temperature. The present results demonstrate a site for the central hypnotic action of adenosine, and a functional role for adenosine A1 receptors in the hypothalamus.
Article
The dose-response effects of intracerebroventricular (ICV) infusion of the pyrimidine ribonucleosides cytidine and uridine and the purine ribonucleoside adenosine on sleep and wakefulness (W) in rats were examined and compared. All three drugs were administered at doses of 1,10, and 100 nmol in volumes of 5 μl, with control animals receiving equivolumetric infusions of 0.9% saline. Treatment with 1 nmol cytidine significantly increased W and decreased both deep slow wave sleep (S2) and total sleep (TS) during both the 3–6 and 0–6 h recording periods. In addition, this dose of cytidine significantly increased light slow wave sleep (S1) during the first 3 h of recording. The 10 nmol dose of cytidine increased W and decreased TS during the 0–6 h recording. ICV administration of uridine produced no significant changes in sleep and W at any dose during any of the recording periods examined. In contrast, adenosine exhibited significant hypnotic effects at all doses examined. All three doses of adenosine significantly reduced W and increased TS during both the 0–3 and 0–6 h recording periods. The 1 and 100 nmol doses of adenosine also significantly increased S2 during both the 0–3 and 0–6 h periods. In addition, the 100 nmol dose of adenosine significantly decreased W and increased both S2 and TS during the second 3 h of recording. Both the 1 and 100 nmol doses of adenosine also significantly reduced the latencies to the onset of rapid eye movement (REM) sleep. These data demonstrate that pyrimidine ribonucleosides do not produce hypnotic effects similar to those of adenosine and, in the case of cytidine, can actually suppress sleep. In addition, adenosine has been shown to significantly increase TS, primarily through an enhancement of S2, and decrease W at a dose as low as 1 nmol. The implications of these results with respect to the role of ribonucleosides, particularly adenosine, in the processes of sleep and W are discussed.
Article
This study examined the effects of tetrahydrocannabinols on sleep-wake states, and especially on paradoxical sleep (PS), in rats bearing chronically implanted EEG and EMG electrodes. Greatest attention was given to Δ9-tetrahydrocannabinol (Δ9-THC), but Δ8-tetrahydrocannabinol and marihuana extract distillate were also studied. These agents in i.p. doses of 5 and 10 mg/kg reduced PS in rats non-deprived (ND) of PS, caused an apparent dissociation of phasic and tonic events of PS in PS-deprived (PSD) rats, and tended to decrease slow-wave sleep and increase wakefulness. No PS rebound was detected during 5 post-drug days in ND rats. In PSD rats the normal PS rebound was replaced by a form of “incomplete PS” characterized by tonic hippocampal theta rhythm, absence of muscle activity and continuous cortical spindling in the absence of normal phasic activity. The effect of 10 mg/kg of Δ9-THC administered daily for 20 days was initially to suppress PS; this was followed by rapid development of tolerance to effects on both sleep and behavior. Partial tolerance remained upon retesting at the 13th withdrawal day. When Δ9-THC was withdrawn no PS rebound occurred in rats. In preliminary experiments in cats, single doses of Δ9-THC (10 mg/kg i.p.) caused a clear-cut inhibition of PS in both ND and PSD cats which was followed by a significant PS rebound on the first post-drug day.
Article
The isolation and elucidation of the structures of Δ1-tetrahydrocannabinol (Δ1-THC), cannabigerol, cannabichromene, and cannabicyclol are described. A facile conversion of cannabidiol into Δ1-THC takes place on treatment with boron trifluoride etherate. The absolute configuration of the chiral centers at C-3 and C-4 of Δ1-THC is established as R.
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
Cannabinoid receptor mRNA was localized in adult rat brain by 35S-tailed oligonucleotide probes and in situ hybridization histochemistry. Labelling is described as uniform or non-uniform depending on the relative intensities of individual cells expressing cannabinoid receptor mRNA within a given region or nucleus. Uniform labelling was found in the hypothalamus, thalamus, basal ganglia, cerebellum and brainstem. Non-uniform labelling that resulted from the presence of cells displaying two easily distinguishable intensities of hybridization signals was observed in several regions and nuclei in the forebrain (cerebral cortex, hippocampus, amygdala, certain olfactory structures). Olfactory-associated structures, basal ganglia, hippocampus, and cerebellar cortex displayed the heaviest amounts of labelling. Many regions that displayed cannabinoid receptor mRNA could reasonably be identified as sources for cannabinoid receptors on the basis of well documented hodologic data. Other sites that were also clearly labelled could not be assigned as logical sources of cannabinoid receptors. The localization of cannabinoid receptor mRNA indicates that sensory, motor, cognitive, limbic, and autonomic systems should all be influenced by the activation of this receptor by either exogenous cannabimimetics, including marijuana, or the yet unknown endogenous "cannabinoid" ligand.
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
Interactions of anandamide (N-arachidonylethanolamide), an endogenous compound for cannabinoid receptors, with the receptors for 5-hydroxytryptamine (5-HT), benzodiazepine, and gamma-aminobutyric acid(A) (GABA[A]) receptors in bovine synaptic membrane were examined. Anandamide decreased the 5-HT receptor bindings at concentrations of 1-100 microM, although it did not cause any change in benzodiazepine or GABA(A) receptor bindings. A high concentration of anandamide, 100 microM, significantly decrease both [3H]5-HT and [3H]ketanserin bindings. The present study revealed that the pharmacological activity of anandamide might be partially mediated through the 5-HT receptor.
Article
The potent analgesic effects of cannabis-like drugs and the presence of CB1-type cannabinoid receptors in pain-processing areas of the brain and spinal cord indicate that endogenous cannabinoids such as anandamide may contribute to the control of pain transmission within the central nervous system (CNS). Here we show that anandamide attenuates the pain behaviour produced by chemical damage to cutaneous tissue by interacting with CB1-like cannabinoid receptors located outside the CNS. Palmitylethanolamide (PEA), which is released together with anandamide from a common phospholipid precursor, exerts a similar effect by activating peripheral CB2-like receptors. When administered together, the two compounds act synergistically, reducing pain responses 100-fold more potently than does each compound alone. Gas-chromatography/mass-spectrometry measurements indicate that the levels of anandamide and PEA in the skin are enough to cause a tonic activation of local cannabinoid receptors. In agreement with this possibility, the CB1 antagonist SR141716A and the CB2 antagonist SR144528 prolong and enhance the pain behaviour produced by tissue damage. These results indicate that peripheral CB1-like and CB2-like receptors participate in the intrinsic control of pain initiation and that locally generated anandamide and PEA may mediate this effect.
Article
In this study we have assessed the effect of the intracerebroventricular administration of anandamide (ANA) as well as its precursor metabolite arachidonic acid (AA), on the sleep-wakefulness cycle, memory formation, locomotor activity and pain perception. Our results have indicated that ANA strikingly increases slow-wave sleep (SWS)2 and rapid-eye movement (REM) sleep at the expense of wakefulness (W); while deteriorating memory consolidation. ANA also increases locomotor activity but does not modify pain perception threshold. In contrast, AA increases W and reduces SWS2, while deteriorating memory consolidation and increasing locomotor activity. AA has no effect on pain perception. These results suggest that the brain cannabinoid system participates in the modulation of the vigilance states and mnemonic processes. Additionally, they suggest that the effect on pain perception may be a peripheral rather than a central effect.
Article
The CB1 cannabinoid receptor in brain is a G-protein-coupled receptor that exists as a protein possessing seven transmembrane helices that span the membrane. The intracellular surface is able to interact with f1p4oteins of the Gi/o family to regulate effector proteins, including adenylate cyclase, Ca2+ channels, and K+ channels, and to stimulate the mitogen-activated protein kinase pathway. The CB1 cannabinoid receptor recognizes three classes of agonist ligands: cannabinoid, eicosanoid, and aminoalkylindole. These agonist subtypes may interact with the CB1 cannabinoid receptor by some common points of association, yet may have subtle differences in the way that they interact with the receptor protein. This may be evident in the allosteric regulation by monovalent cations and individual agonists. The juxtamembrane region of the C-terminal is able to activate G-proteins. It is proposed that conformational changes in the receptor induced by agonist ligands may alter the conformation or exposure of the juxtamembrane C-terminal region extending from helix VII.
Article
We employed the CB1 cannabinoid receptor antagonist SR 141716A (3 mg/kg, i.p.) to investigate whether behavioural effects induced in rats by anandamide, an endogenous cannabinoid (20 mg/kg, i.p.), were mediated by the cannabinoid CB1 receptor. Anandamide reduced ambulatory (67%) and non-ambulatory activities (rearing and grooming, 84% and 90% respectively), with a strong cataleptic effect, produced hypothermia (about -1 degree C) and hindlimb splaying, and reduced defecation (79%). It did not significantly increase either the tail-flick or hot-plate latencies. Except for the decreased defecation, these responses were all blocked by SR 141716A. Although only single doses of the agonist and antagonist were used, the findings indicate that these behavioural effects are probably mediated by an interaction with cannabinoid CB1 receptors.
Article
The purpose of this review is to discuss the cellular synthesis and inactivation of two putative endogenous ligands of the cannabinoid receptor, N-arachidonylethanolamine (AEA) and 2-arachidonylglycerol (2-AG). Both ligands are synthesized by neurons and brain tissue in response to increased intracellular calcium concentrations. Both ligands are substrates for fatty acid amide hydrolase (FAAH). Both AEA and 2-AG bind to the neuronal form of the cannabinoid receptor (CB1). AEA binds the receptor with moderate affinity and has the characteristics of a partial agonist, whereas, 2-AG binds with low affinity but exhibits full efficacy. Two possible physiological roles of the endocannabinoids and the CB1 receptor are discussed: the regulation of gestation and the regulation of gastrointestinal motility.
Article
The effect of intracerebellar microinfusion of antisense oligodeoxynucleotide to Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and other naturally occurring cannabinoid receptor (CB(1)) mRNA on Delta(9)-THC-induced motor impairment was investigated in mice. Delta(9)-THC (15-30 microgram/microliter intracerebellar) resulted in a significant motor impairment in a dose-related manner. The intracerebellar pretreatment with antisense oligodeoxynucleotide (3.0 microgram/100 nl/12 h; six administrations/mouse) virtually abolished Delta(9)-THC (15 and 25 microgram/1 microliter intracerebellar)-induced motor impairment. However, intracerebellar pretreatment with the mismatched oligodeoxynucleotide in exactly the same manner as the antisense was completely ineffective in altering the Delta(9)-THC-induced motor impairment. These results strongly suggest the involvement of CB(1) receptor in the expression of Delta(9)-THC-induced motor impairment. The intracerebellar microinfusion of adenosine A(1)-selective agonist, N(6)-cyclohexyladenosine (CHA) (4 ng/100 nl) significantly enhanced Delta(9)-THC-induced motor impairment, suggesting a cerebellar A(1) adenosinergic modulation of motor impairment. A pretreatment with the antisense and the mismatched oligodeoxynucleotide also markedly attenuated and did not alter, respectively, the cerebellar A(1) adenosinergic modulation (enhancement) of Delta(9)-THC-induced motor impairment. There was no change in the normal motor coordination due to intracerebellar pretreatment with antisense and its mismatch, in the presence as well as absence of intracerebellar CHA indicating the selectivity of interactions with Delta(9)-THC. The Delta(9)-THC-induced motor incoordination was also significantly enhanced dose-dependently by systemic (i.p.) ethanol administration suggesting behavioral synergism between the two psychoactive drugs. Pretreatment (intracerebellar) with pertussis toxin (PTX) markedly attenuated Delta(9)-THC- and Delta(9)-THC+CHA-induced motor incoordination suggesting coupling of CB(1) receptor to PTX-sensitive G-protein (G(i)/G(o)). These data suggested co-modulation by cerebellar cannabinoid and adenosine system of Delta(9)-THC-induced motor impairment. Conversely, the results in the present study also suggested co-modulation by cerebellar adenosine A(1) and CB(1) receptors of ethanol-induced motor impairment, thereby indicating a possible common signal transduction pathway in the expression of motor impairment produced by Delta(9)-THC as well as ethanol.