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Anandamida modulates sleep and memory in rats
Abstract
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.
... Because the localization of the CB 1 cannabinoid receptor was primarily into the central nervous as well as into sleep-related brain areas, substantial studies have been directed toward identifying the putative effects of either agonist or antagonist of CB 1 cannabinoid receptor influencing the sleep-wake cycle. Overall, summarizing the available literature, the activation of CB 1 cannabinoid receptor by both endogenous ligands increases REMS while alertness is decreased (Murillo-Rodriguez et al., 2003;Murillo-Rodrıǵuez et al., 1998;Pérez-Morales et al., 2013). Opposite findings have been reported if CB 1 cannabinoid receptor antagonist, including SR141716A, is administered (Puskar et al., 2021). ...
... Opposite findings have been reported if CB 1 cannabinoid receptor antagonist, including SR141716A, is administered (Puskar et al., 2021). It is worthy to highlight that the enhancement in sleep observed after the administrations of AEA was prevented by the injection of SR141716A (Murillo-Rodriguez et al., 2003;Murillo-Rodrıǵuez et al., 1998). Despite the current data in regard to the role of the CB 1 cannabinoid receptor on sleep control, limited evidence is available to discuss the effects of the CB 2 cannabinoid receptor on sleep modulation. ...
... Due to the mapping of AEA and 2-AG in sleep-related brain areas (Kendall & Yudowski, 2017;Rusjan et al., 2013), their putative role on sleep modulation has been the focus of interest (Kesner & Lovinger, 2020;Murillo-Rodríguez et al., 2016;Murillo-Rodríguez et al., 2020a, b). Major findings have shown that central or systemic administration of either AEA or 2-AG enhances SWS and REMS while waking is diminished (Murillo-Rodriguez et al., 2003;Murillo-Rodrıǵuez et al., 1998;Pérez-Morales et al., 2013). As previously mentioned, the sleep-inducing effects of AEA or 2-AG seem to be related to the activation of the CB 1 cannabinoid receptors. ...
... 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). ...
... 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). ...
... transporters, synthesizing/degrading enzymes, etc.) in sleep modulation, the current report provides further evidence for the role of AA-5-HT in sleep control. At this date, the neuromolecular role of the endocannabinoid system in sleep-wake cycle regulation has provided important insights regarding the involvement of AEA, CB 1 cannabinoid receptor, AMT, as well as FAAH (Murillo-Rodríguez et al., 1998, 2003, 2007b, 2008a, 2011aHerrera-Solis et al., 2010;Pava et al., 2014Pava et al., , 2016Rueda-Orozco et al., 2010). However, the identification of new compounds targeting the endocananbinoid system will help validating the role of this system in sleep control highlighting the most pertinent drug with highest efficiency and lowest side effects in animal models (Lauria et al., 2015;Nimczick and Decker, 2015;Bertini et al., 2016;Aizpurua-Olaizola et al., 2017;Chicca et al., 2017). ...
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.
... Similar to 2-AG, AEA levels are also modulated by the circadian rhythm, where it was found that AEA levels were three times higher immediately after waking compared to before sleep [111]. Extensive in vivo studies have shown that the administration of AEA in humans [112] and rats [113][114][115][116] increases SWS and NREM sleep while inhibiting wakefulness. Murillo-Rodriguez and his colleagues have also found that microinjections of AEA in rats increased adenosine levels in the basal forebrain and increased SWS [98], suggesting that the somnogenic effects of AEA may partly be due to the modulation of extracellular adenosine concentrations. ...
... Several studies have found that SR141716A, as an inverse agonist of CB 1 , blocks the effects of other CB 1 -acting cannabinoids, including CBD [189], THC [190], AEA [116], and 2-AG [191]. Interestingly, SR141716A inhibits the effects of AEA-induced sleep [116], while another study [113] found that intraperitoneal administration of SR141716A (0.1, 0.3, 1, 3, & 10 mg/kg) increased wakefulness while inhibiting SWS and REM sleep. Owing to the wake-promoting effects of SR141716A, it could potentially be used for the treatment of narcolepsy and excessive somnolence [9]. ...
Sleep is an essential biological phase of our daily life cycle and is necessary for maintaining homeostasis, alertness, metabolism, cognition, and other key functions across the animal kingdom. Dysfunctional sleep leads to deleterious effects on health, mood, and cognition, including memory deficits and an increased risk of diabetes, stroke, and neurological disorders. Sleep is regulated by several brain neuronal circuits, neuromodulators, and neurotransmitters, where cannabinoids have been increasingly found to play a part in its modulation. Cannabinoids, a group of lipid metabolites, are regulatory molecules that bind mainly to cannabinoid receptors (CB1 and CB2). Much evidence supports the role of cannabinoid receptors in the modulation of sleep, where their alteration exhibits sleep-promoting effects, including an increase in non-rapid-eye movement sleep and a reduction in sleep latency. However, the pharmacological alteration of CB1 receptors is associated with adverse psychotropic effects, which are not exhibited in CB2 receptor alteration. Hence, selective alteration of CB2 receptors is also of clinical importance, where it could potentially be used in treating sleep disorders. Thus, it is crucial to understand the neurobiological basis of cannabinoids in sleep physiology. In this review article, the alteration of the endocannabinoid system by various cannabinoids and their respective effects on the sleep-wake cycle are discussed based on recent findings. The mechanisms of the cannabinoid receptors on sleep and wakefulness are also explored for their clinical implications and potential therapeutic use on sleep disorders.
... Thus, eCB signaling is well positioned to support the highly coordinated neuronal activity that likely promotes the restorative actions of NREM sleep. Direct infusion of eCBs into the cerebral ventricles, hippocampus, or lateral hypothalamus have been shown to promote REM sleep [35][36][37][38] . Thus, it is likely that eCB signaling affects sleep behavior and physiology through cortical and subcortical brain regions, including the suprachiasmatic nucleus [20,39,40] . ...
... Quantification of total sleep time and bout lengths following vehicle or drug treatments are summarized in Supplementary Table 3. Multiple previous studies have shown that increased eCB signaling by direct agonist treatment, or inhibition of MAGL or FAAH, promotes sleep in adult male mice or male rats [30,35] . Whether similar effects are also seen in developing mice or females has not been tested. ...
Sleep is an essential behavior that supports brain function and cognition throughout life, in part by acting on neuronal synapses. The synaptic signaling pathways that mediate the restorative benefits of sleep are not fully understood, particularly in the context of development. Endocannabinoids (eCBs) including 2-arachidonyl glycerol (2-AG) and anandamide (AEA), are bioactive lipids that activate cannabinoid receptor, CB1, to regulate synaptic transmission and mediate cognitive functions and many behaviors, including sleep. We used targeted mass spectrometry to measure changes in forebrain synaptic eCBs during the sleep/wake cycle in juvenile and adolescent mice of both sexes. We find that eCBs lack a daily rhythm in juvenile mice, while in adolescents AEA and related OEA are increased during the sleep phase in a circadian manner. Next, we manipulated the eCB system using selective pharmacology and measured the effects on sleep behavior in developing and adult mice of both sexes using a non-invasive piezoelectric home-cage recording apparatus. Enhancement of eCB signaling through inhibition of 2-AG or AEA degradation, increased dark phase sleep amount and bout length in developing and adult males, but not in females. Inhibition of CB1 by injection of the antagonist AM251 reduced sleep time and caused sleep fragmentation in developing and adult males and females. Our data suggest that males are more sensitive to the sleep promoting effects of enhanced eCBs but that tonic eCB signaling supports sleep behavior through multiple stages of development in both sexes. This work informs the further development of cannabinoid-based therapeutics for sleep disruption.
... In the nucleus accumbens, pre-frontal cortex, striatum, and hippocampus, structures associated with limbic and sensorimotor system functions such as learning and memory and action control, 2-AG and AEA show inverse diurnal rhythms, with the former higher during the light-phase and the latter higher during the dark-phase (Valenti et al., 2004;Matias et al., 2008), indicating the distinct role that eCBS play in sleep-wake is complex and needs further elucidation. One possible explanation for the opposing changes in AEA and 2-AG levels during light and dark periods could be that while AEA may promote sleep (Murillo-Rodriguez et al., 1998Rueda-Orozco et al., 2010) 2-AG may promote wakefulness (Prospéro-García et al., 2016). The diurnal fluctuation of eCB levels in limbic and sensorimotor structures may reflect their complex role in awake-behavior related learning, e.g., associative learning related to action control (Lovinger and Mathur, 2012;Morena et al., 2014;Gremel et al., 2016;Mateo et al., 2017;Lupica and Hoffman, 2018), and sleep-behavior related learning, e.g., hippocampal-dependent memory consolidation (Riedel and Davies, 2005;De Oliveira Alvares et al., 2008;Yim et al., 2008;Busquets-Garcia et al., 2016). ...
... Systemic administration of AEA is known to promote sleep (Mechoulam et al., 1997;Murillo-Rodriguez et al., 1998, an effect which is partially due to its action in the pedunculopontine tegmental nucleus (PPTg), a hindbrain region implicated in sleep and arousal mechanisms (Murillo-Rodriguez et al., 2001). 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). ...
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.
... Pharmacological evidence from experiments on central or peripheral administrations has shown that elements of the endocannabinoid family participate in sleep control. For example, pioneer studies by the laboratory of Gerard Le Fur [111], Vincent Santucci, and coworkers demonstrated that the systemic injections of the CB 1 cannabinoid receptor antagonist SR 141716A (0.1, 0.3, 1, 3 and 10 mg/Kg) increased the time spent in wakefulness (W) while decreased slow-wave sleep (SWS) and REMS whereas opposite results were described by our group in 1998 after icv injection of anandamide [112]. Remarkably, the sleep-inducing effects of anandamide were blocked by SR141716A [113]. ...
... Anandamide and 2-AG promote sleep via activation of the CB 1 cannabinoid receptor [92,112,113]. The available literature has indicated that the CB 1 cannabinoid receptor in aged rats seems to be decreased [125,133]. ...
Aging is an inevitable process that involves changes along life in multiple neurochemical, neuroanatomical, hormonal systems, and many others. In addition, these biological modifications lead to an increase in age-related sickness such as cardiovascular diseases, osteoporosis, neurodegenerative disorders, and sleep disturbances, among others that affect activities of daily life. Demographic projections have demonstrated that aging will increase its worldwide rate in the coming years. The research on chronic diseases of the elderly is important to gain insights into this growing global burden. Novel therapeutic approaches aimed for treatment of age-related pathologies have included the endocannabinoid system as an effective tools since this biological system shows beneficial effects in preclinical models. However, and despite these advances, little has been addressed in the arena of the endocannabinoid system as option for treating sleep disorders in aging since experimental evidence suggests that some elements of the endocannabinoid system modulate the sleep-wake cycle. This article addresses this less-studied field, focusing on the likely perspective of the implication of the endocannabinoid system in the regulation of sleep problems reported in aged. We conclude that beneficial effects regarding the putative efficacy of the endocannabinoid system as therapeutic tools in aging is either inconclusive or still missing.
... The relationship between the cannabinergic system and cognitive processes such as learning and memory has been extensively explored in different models including rodents (for reviews, Goodman and Packard, 2015;Busquets-Garcia et al., 2015). For example, we know that systemic and intracerebral administrations of CB1r agonists impair the consolidation of spatial (Hampson and Deadwyler, 1998;Rueda-Orozco et al., 2008;Abush and Akirav, 2010;Wise et al., 2011;Galanopoulos et al., 2014) and fear memories (Murillo-Rodriguez et al., 1998Mać kowiak et al., 2009;Kruk-Slomka et al., 2016). On the other hand, previous studies in our laboratory have shown that the CB1r receptor (mRNA and protein) fluctuates in the hippocampus of rats following the light-dark cycle, and it exhibits the highest concentration during the light hours (Rueda-Orozco et al., 2008). ...
... In contrast, the effects of ODA were independent of the light-dark cycle and exclusive for intra-hippocampal administrations. Previous reports indicate that intra-hippocampal administrations of AEA or systemic injections of TCH impaired the consolidation of contextual fear memories (Murillo-Rodriguez et al., 1998;Mishima et al., 2001). Our data indicate that cannabinergic activation also affects cued fear memories but in a light-dark cycle dependent way. ...
... The EC system functions in a broad range of physiological processes and behaviors, such as neurogenesis, neural development, immune function, metabolism and energy homeostasis, pain, emotional state, arousal, sleep, stress reactivity, synaptic plasticity, learning, and reward processing of many drugs of abuse, including alcohol (Basavarajappa, 2015;Basavarajappa, Nagre, Xie, & Subbanna, 2014;Fernández-Ruiz, Berrendero, Hernandez, & Ramos, 2000;Murillo-Rodriguez et al., 1998Murillo-Rodriguez, Blanco-Centurion, Sanchez, Piomelli, & Shiromani, 2003;Murillo-Rodriguez et al., 1998;Pacher & Kunos, 2013;Pertwee, 2001;. ...
... The EC system functions in a broad range of physiological processes and behaviors, such as neurogenesis, neural development, immune function, metabolism and energy homeostasis, pain, emotional state, arousal, sleep, stress reactivity, synaptic plasticity, learning, and reward processing of many drugs of abuse, including alcohol (Basavarajappa, 2015;Basavarajappa, Nagre, Xie, & Subbanna, 2014;Fernández-Ruiz, Berrendero, Hernandez, & Ramos, 2000;Murillo-Rodriguez et al., 1998Murillo-Rodriguez, Blanco-Centurion, Sanchez, Piomelli, & Shiromani, 2003;Murillo-Rodriguez et al., 1998;Pacher & Kunos, 2013;Pertwee, 2001;. ...
... In this regard, pharmacological or molecular manipulation of the endocannabinoid system in sleep has been studied . 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]). ...
... 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]. ...
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.
... Regarding PEA, it also increases wakefulness when administered into the lateral hypothalamus, and into the dorsal raphe nucleus of rats, at the expense of NREM and REM sleep (Murillo-Rodriguez et al., 2011). In animal models, eCBs, such as AEA and 2-AG, reduce wakefulness while increasing sleep Murillo-Rodrıíguez et al., 1998;Pérez-Morales et al., 2013). In addition, SR141716a blockade of the CB1R increases wakefulness in rats (Santucci et al., 1996). ...
... To determine if AEA is involved in sleep modulation, several studies have been carried out. For example, it has been shown that AEA increases both NREM and REM sleep in rats, when injected into the cerebral ventricles (Murillo-Rodrıíguez et al., 1998). Systemic administration of AEA in rats induces both an increase in adenosine in the basal forebrain and NREM sleep 3 h after its injection. ...
... Manipulations of the endocannabinoid system have proved informative on mechanisms of sleep behavior. Interestingly, the direct infusion of eCBs into the cerebral ventricles, hippocampus, or lateral hypothalamus has been shown to promote rapid eye movement (REM) sleep [37][38][39][40]. Additional studies highlight the role of eCBs in both NREM and REM sleep [9]. ...
Sleep disruption is an expected component of aging and neurodegenerative conditions, including Alzheimer’s disease (AD). Sleep disruption has been demonstrated as a driver of AD pathology and cognitive decline. Therefore, treatments designed to maintain sleep may be effective in slowing or halting AD progression. However, commonly used sleep aid medications are associated with an increased risk of AD, highlighting the need for sleep aids with novel mechanisms of action. The endocannabinoid system holds promise as a potentially effective and novel sleep-enhancing target. By using pharmacology and genetic knockout strategies, we evaluated fatty acid amide hydrolase (FAAH) as a therapeutic target to improve sleep and halt disease progression in a transgenic Tau P301S (PS19) model of Tauopathy and AD. We have recently shown that PS19 mice exhibit sleep disruption in the form of dark phase hyperarousal as an early symptom that precedes robust Tau pathology and cognitive decline. Acute FAAH inhibition with PF3845 resulted in immediate improvements in sleep behaviors in male and female PS19 mice, supporting FAAH as a potentially suitable sleep-promoting target. Moreover, sustained drug dosing for 5–10 days resulted in maintained improvements in sleep. To evaluate the effect of chronic FAAH inhibition as a possible therapeutic strategy, we generated FAAH−/− PS19 mice models. Counter to our expectations, FAAH knockout did not protect PS19 mice from progressive sleep loss, neuroinflammation, or cognitive decline. Our results provide support for FAAH as a novel target for sleep-promoting therapies but further indicate that the complete loss of FAAH activity may be detrimental.
... 1. Resting wake EEG power before sleep (Acute Effects of CBN). Resting wake EEG power during the KDT prior to sleep: delta (1-4.5 Hz), theta (4.5-8 Hz), alpha (8-12 Hz), sigma (12)(13)(14)(15), beta (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and gamma (25-40 Hz) frequency ranges. Power spectral analysis is applied to EEG signals from polysomnography, after artefacts are detected and removed. ...
... Cannabinoid 1 (CB 1 ) receptors are present in various brain regions involved in the sleep-wake cycle [16,42]. Previous work in animal models demonstrates that the activation of the CB 1 receptors increases slow wave and REM sleep while decreasing wakefulness [43]. Further investigations also indicate that antagonists to the CB 1 receptor cause increased wakefulness with reductions in slow wave and REM sleep [44], further supporting the activation of CB 1 receptors to improve sleep quality. ...
Background:
The endocannabinoid system is active in nervous and immune cells and involves the expression of two cannabinoid receptor genes (CB1 and CB2), along with endogenous endocannabinoid ligands, 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide), and their synthetic enzymes. Cannabidiol (CBD) is a non-intoxicating exogenous cannabinoid agonist derived from plants that, at high doses, has received FDA approval as an anticonvulsant for epileptic seizures, and at low doses is marketed as a food-grade supplement for improved mental health, sleep quality, and immunological function. At present, the predominance of published CBD clinical research has focused on ameliorative or disease-specific intervention, with few trials investigating CBD effects in healthy populations.
Methods:
This clinical study aimed to investigate the effects of 8 weeks of 50 mg oral CBD on mental health, sleep quantity and quality, and immune cell function in healthy, college-aged individuals. Twenty-eight participants (average age 25.9 ± 6.1 y) were randomized to receive either daily oral capsules of 50 mg of CBD (CB, n = 14) or a calorie-matched placebo (CN, n = 14). Participants completed pre- and post-intervention assessments, including anthropometric measurements, mental health surveys, sleep analysis, and immunological function assessments.
Results:
After completing the 8-week intervention, there were no significant changes in body weight and BMI (CN: 1.09 ± 0.89%: CB: 1.41 ± 1.07%), or body fat percentage (CN: 9.01 ± 7.51%: CB: 8.57 ± 7.81%), respectively (values are % change pre to post, p > 0.05). There were also no significant differences between CB and CN groups with respect to mental health measures, sleep quantity, or circulating immunophenotype as a result of the intervention. However, the CB group experienced significant improvements in sleep quality measured objectively using a sleep questionnaire (p = 0.0023) and enhanced Natural Killer (NK) immune cell function assessed in situ (p = 0.0125).
Conclusions:
Eight weeks of daily 50 mg CBD may improve sleep quality, and NK immunosurveillance in healthy, younger adults.
... 1. Resting wake EEG power before sleep (Acute Effects of CBN). Resting wake EEG power during the KDT prior to sleep: delta (1-4.5 Hz), theta (4.5-8 Hz), alpha (8-12 Hz), sigma (12)(13)(14)(15), beta (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and gamma (25-40 Hz) frequency ranges. Power spectral analysis is applied to EEG signals from polysomnography, after artefacts are detected and removed. ...
Objective
Insomnia is the most prevalent sleep disorder, with few effective pharmacotherapies. Anecdotal reports and recent preclinical research suggest that cannabinol (CBN), a constituent of Cannabis sativa derived from delta-9-tetrahydrocannabinol, could be an effective treatment. Despite this, the isolated effects of CBN on sleep have yet to be systematically studied in humans.
Methods
The present protocol paper describes a randomised, double-blind, placebo-controlled, single-dose, three-arm, cross-over, proof-of-concept study which investigates the effects of CBN on sleep and next-day function in 20 participants with clinician-diagnosed insomnia disorder and an Insomnia Severity Index Score ≥15. Participants receive a single fixed oral liquid dose of 30 mg CBN, 300 mg CBN and matched placebo, in random order on three treatment nights; each separated by a 2-week wash-out period. Participants undergo overnight sleep assessment using in-laboratory polysomnography and next-day neurobehavioural function tests. The primary outcome is wake after sleep onset minutes. Secondary outcomes include changes to traditional sleep staging, sleep-onset latency and absolute spectral power during non-rapid eye movement (NREM) sleep. Tertiary outcomes include changes to sleep spindles during NREM sleep, arousal indices, absolute spectral power during REM sleep and subjective sleep quality. Safety-related and exploratory outcomes include changes to next-day simulated driving performance, subjective mood and drug effects, postural sway, alertness and reaction time, overnight memory consolidation, pre and post-sleep subjective and objective sleepiness; and plasma, urinary, and salivary cannabinoid concentrations. The study will provide novel preliminary data on CBN efficacy and safety in insomnia disorder, which will inform larger clinical trials.
Ethics and dissemination
Human Research Ethics Committee approval has been granted by Bellberry (2021-08-907). Study findings will be disseminated in a peer-reviewed journal and at academic conferences.
Trial registration number
NCT05344170 .
... Accordingly, we found a significant increase in K + -evoked glutamate efflux in JWH-018 mice (see above). Moreover, intracerebroventricular administration of AEA increases locomotor activity (Murillo-Rodríguez et al., 1998) and ...
Background and Purpose
Psychotic disorders have been reported in long‐term users of synthetic cannabinoids. This study aims at investigating the long‐lasting effects of repeated JWH‐018 exposure.
Experimental Approach
Male CD‐1 mice were injected with vehicle, JWH‐018 (6 mg·kg⁻¹), the CB1‐antagonist NESS‐0327 (1 mg·kg⁻¹) or co‐administration of NESS‐0327 and JWH‐018, every day for 7 days. After 15 or 16 days washout, we investigated the effects of JWH‐018 on motor function, memory, social dominance and prepulse inhibition (PPI). We also evaluated glutamate levels in dialysates from dorsal striatum, striatal dopamine content and striatal/hippocampal neuroplasticity focusing on the NMDA receptor complex and the neurotrophin BDNF. These measurements were accompanied by in vitro electrophysiological evaluations in hippocampal preparations. Finally, we investigated the density of CB1 receptors and levels of the endocannabinoid anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) and their main synthetic and degrading enzymes in the striatum and hippocampus.
Key Results
The repeated treatment with JWH‐018 induced psychomotor agitation while reducing social dominance, recognition memory and PPI in mice. JWH‐018 disrupted hippocampal LTP and decreased BDNF expression, reduced the synaptic levels of NMDA receptor subunits and decreased the expression of PSD95. Repeated exposure to JWH‐018, reduced hippocampal CB1 receptor density and induced a long‐term alteration in AEA and 2‐AG levels and their degrading enzymes, FAAH and MAGL, in the striatum.
Conclusion and Implications
Our findings suggest that repeated administration of a high dose of JWH‐018 leads to the manifestation of psychotic‐like symptoms accompanied by alterations in neuroplasticity and change in the endocannabinoid system.
... NADA activates the TRPV1 channel with an EC50 of approximately of 50 nM. The high potency makes it the putative endogenous TRPV1 agonist [26]. Anandamide has also been found to activate TRPV1 on sensory neuron terminals, and subsequently cause vasodilation. ...
Whether chasing down dinner, pushing a stroller up a hill or running errands for a neighbor, we can take joy in the effort. And the more physically active you are, the more rewarding these experiences become. One of the ways that regular exercise changes your brain is by increasing the density of binding sites for endocannabinoids. Spring-like leg behavior is a general feature of mammalian bouncing gaits, such as running and hopping. Although increases in step frequency at a given running speed are known to increase the stiffness of the leg spring (kleg) in non-amputees, little is known about stiffness regulation in unilateral transfemoral amputees. Thus Consequently, the unilateral transfemoral amputees attained the desired step frequency in the unaffected limb, but were unable to match the three highest step frequencies using their affected limbs
... [7][8][9] Anandamide is the partial agonist on CB 1 and CB 2 receptors with a higher affinity towards CB 1 receptors, while 2-AG is a complete agonist of CB 1 and CB 2 receptors. 10,11 The CB 1 receptors are predominantly expressed in the nerve terminals and on neuroglia. Whereas CB 2 receptors are located majorly in the peripheral region of the body, immune cells, and microglia of the AD brain. ...
Fatty acid amide hydrolase (FAAH) is a prominent enzyme of the endocannabinoid system that degrades endogenous cannabinoid anandamide and oleamide. These lipid amides are involved in reducing neuroinflammation, pain and regulation of other neurological-related activities including feeding behaviours, sleep patterns, body temperature, memory processes and locomotory activity. Many of these activities are affected in most neurological disorders. Increased levels of brain FAAH expressions are speculated to correlate with decreased levels of lipid amides and increased AD-related symptoms. Thus, inhibition of FAAH shows promising potential in amelioration of symptoms associated with Alzheimer's disease (AD). The review aims at establishing the detrimental role of increased FAAH expression in AD and highlights the translational potential and therapeutic application of FAAH inhibitors in AD.
... 2-AG mediates major forms of eCB-dependent plasticity, such as DSI, DSE and mGluR-dependent LTD (Castillo et al., 2012;Tanimura et al., 2010;Yoshino et al., 2011). However, AEA has been implicated in cortical up-sate activity, sleep stability and memory (Busquets-Garcia et al., 2011;Murillo-Rodriguez et al., 1998;Pava et al., 2014). Our results indicate that AEA but not 2-AG exerts tonic action during homeostatic scaling-down (Fig. 2). ...
Neurons express overlapping homeostatic mechanisms to regulate synaptic function and network properties in response to perturbations of neuronal activity. Endocannabinoids (eCBs) are bioactive lipids synthesized in the post-synaptic compartments to regulate synaptic transmission, plasticity, and neuronal excitability primarily through retrograde activation of pre- synaptic cannabinoid receptor type 1 (CB1). The eCB system is well-situated to regulate neuronal network properties and coordinate pre- and post-synaptic activity. However, the role of the eCB system in homeostatic adaptations to neuronal hyperactivity is unknown. To address this issue, we used western blot and targeted lipidomics to measure adaptations in eCB system to bicuculline (BCC)-induced chronic hyperexcitation in mature (>DIV21) cultured rat cortical neurons, and used multielectrode array recording and live-cell imaging of glutamate dynamics to test the effects of pharmacological manipulations of eCB on network activities. We show that BCC-induced chronic hyperexcitation triggers homeostatic downscaling and a coordinated adaptation to enhance tonic eCB signaling. Hyperexcitation triggers first the downregulation of fatty acid amide hydrolase (FAAH), the lipase that degrades the eCB anandamide, then an accumulation of anandamide and related metabolites, and finally a delayed upregulation of surface and total CB1. Additionally, we show that BCC-induced downregulation of surface AMPA-type glutamate receptors (AMPARs) and upregulation of CB1 occur through independent mechanisms. Finally, we show that endocannabinoids support baseline network activities before and after downscaling and is engaged to suppress network activities during adaptation to hyperexcitation. We discuss the implications of our findings in the context of downscaling and homeostatic regulation of oscillatory network activities.
Significance statement
Neurons are remarkably resilient to perturbations in network activities thanks to the expression of overlapping homeostatic adaptations. In response to network hyperactivity or silencing, neurons respond through regulating excitatory and inhibitory post-synaptic neurotransmitter receptors density, probability of pre-synaptic neurotransmitter release, and/or membrane excitability. The endocannabinoid system is a prominent signaling pathway at many synapses that is known to be involved in multiple forms of short- and long-term synaptic plasticity. Here we find that components of the endocannabinoid system are upregulated in response to chronic hyperexcitation of cultured cortical neurons, and that endocannabinoid signaling is required to maintain network activity but also suppresses network events during hyperexcitation. This work supports a novel tonic homeostatic function for the endocannabinoid system in neurons.
... Multiple previous studies have shown that increased eCB signaling by direct agonist treatment, or inhibition of MAGL or FAAH, promotes sleep in adult male mice or rats (Murillo-Rodriguez et al., 1998;Pava et al., 2016). Whether similar effects are also seen in developing mice or females has not been tested. ...
Sleep is an essential behavior that supports brain function and cognition throughout life, in part by acting on neuronal synapses. The synaptic signaling pathways that mediate the restorative benefits of sleep are not fully understood, particularly in the context of development. Endocannabinoids (eCBs) including 2-arachidonyl glycerol (2-AG) and anandamide (AEA), are bioactive lipids that activate cannabinoid receptor, CB1, to regulate synaptic transmission and mediate cognitive functions and many behaviors, including sleep. We used targeted mass spectrometry to measure changes in forebrain synaptic eCBs during the sleep/wake cycle in developing and adult mice. We find that eCBs are downregulated in response to acute sleep deprivation in juvenile mice, while in young adults eCBs are upregulated during the sleep phase in a circadian manner. Next we manipulated the eCB system using selective pharmacology and measured the effects on sleep behavior in developing and adult mice of both sexes using a non-invasive piezoelectric home-cage recording apparatus. Enhancement of eCB signaling through inhibition of 2-AG or AEA degradation, increased dark phase sleep amount and bout length in developing and adult males, but not in females. Inhibition of CB1 by injection of the antagonist AM251 reduced sleep time and caused sleep fragmentation in developing and adult males and females. Our data suggest that males are more sensitive to the sleep promoting effects of enhanced eCBs but that tonic eCB signaling supports sleep behavior through multiple stages of development in both sexes. This work informs the further development of cannabinoid-based therapeutics for sleep disruption.
... Les CB augmentent le sommeil par l'intermédiaire d'un lipide, l'oléamide (augmentation des phases lente et paradoxale REM, rapid eye movements), avec pour corollaire une diminution du temps d'éveil [42]. De plus, l'antagoniste CB1 SR141716A augmente l'état d'éveil, suggérant un rôle physiologique du système endoCB dans le contrôle des états de sommeil et de vigilance. ...
... 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. ...
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.
... Moreover, this vulnerability might involve brain areas linked to the control of key homeostatic functions, including as the sleep-wake cycle (Houston et al., 2014;Chen and Baram, 2015). Available data regarding the impact of cannabinoid receptor stimulation and sleep alterations derive from studies conducted in adult animals and with either acute or subchronic treatment designs (Murillo-Rodríguez et al., 1998Altman et al., 2019;Angarita et al., 2016;Furer et al., 2018;Goonawardena et al., 2011Goonawardena et al., , 2015Pava et al., 2014;Prospéro-García et al., 2016). By contrast, the persistent effects of prolonged cannabinoid receptor activation during adolescence on sleep, if any, are unknown. ...
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.
... 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]. ...
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.
... These are formed rapidly from lipid precursors and are released from their source cells upon stimulation and activate cannabinoid receptors on the same or nearby cells or are quickly metabolized (hydrolyzed) by specific serine hydrolase known as fatty acid amide hydrolase [1]. Relevant examples include anandamide, 2-arachidonylglycerol, virodamine, etc. Endocannabinoids seem to be involved in many regulatory functions in animals such as regulation of egg implantation [6], control of sensorimotor and motivational aspects [7], sleep wakefulness cycle, pain perception, memory function, etc. [8]. These perform their actions by interacting with either CB1 or CB2 receptor subtypes, which results in activation of G-proteins (particularly those belonging to G(i/o) family [9]. ...
Purpose of Review
This review gives an overview of the medicinal uses of synthetic cannabinoids and other related aspects on the basis of recent as well as earlier studies that the authors considered relevant to the context and scope of the review.
Recent Findings
Synthetic cannabinoids are laboratory synthesized products eliciting effects way more than their natural counterparts. These compounds are more potent in generating intoxicating effects and are also difficult to be detected in conventional screening tests. Their clinical side effects are also more pronounced than natural cannabinoids, and their antidotes are also not known. However, they are also therapeutically found to be very effective in many health conditions, as these act by interacting with almost ubiquitously distributed cannabinoid receptors (CB1 and CB2) in the human body and by other mechanisms also that do not involve these receptors.
Summary
All the issues related to their appropriate dosage, mode of action, acute and chronic effects in vivo, interaction with other drugs, their metabolism, etc. need much research to be done so that it will be easier to predict their different aspects in human subjects in more appropriate way. Further, development of strict legislation and regulation is required to be done so that their abuse can be curbed, and toxic effects can be reduced, but medicinal benefits and usage can be enhanced.
... That was the case when the FAAH inhibitor URB597 was given systemically or intra-dorsal hippocampus. These results agree with the impaired aversive memory consolidation reported after systemic or intra-dorsal hippocampus infusion of URB597, anandamide or other CB 1 /CB 2 receptor agonists (Castellano et al., 1997;Murillo-Rodríguez et al., 1998;Ma ckowiak et al., 2009;Busquets-Garcia et al., 2011;Segev and Akirav, 2011;Zarrindast et al., 2012;Kuhnert et al., 2013). However, the opposite effect was reported when this drug was given during the consolidation of an inhibitory avoidance memory in rats (Morena et al., 2014). ...
Pharmacological interventions able to modulate a fear memory while it is consolidated could have therapeutic value in tempering those maladaptively overconsolidated. Animal and human studies have shown the intensity of unconditioned stimulus delivered during fear conditioning influences qualitative and quantitative aspects of the memory to be established. By varying the shock intensity used for contextual pairing in rats, here we induced specific and more generalized long-term fear memories to investigate whether, how and where in the brain the cannabidiol (CBD; 3.0–30 mg/kg i.p.) could impair their consolidation and related outcomes. When given immediately after their acquisition, it reduced respectively the conditioned fear expression, and fear generalization, ultrasonic vocalizations at 22-kHz and the relative resistance to extinction. CBD had no effects on short-term fear memory, and its delayed treatment no longer affected the consolidation process. As the dorsal hippocampus (DH) modulates fear memory specificity and generalization, and cannabinoid type-1 (CB1) and type-2 (CB2) receptors contribute to consolidation, we investigated their involvement in CBD effects. Both systemic and intra-DH treatment with the CB1 receptor antagonist/inverse agonist AM251 or the CB2 receptor antagonist/inverse agonist AM630 prevented the disrupting CBD effects on consolidation. Since the CBD effects on the endocannabinoid transmission are probably indirect, we investigated and demonstrated the FAAH inhibitor URB597 induced effects similar to those of CBD when given systemically or intra-DH. Altogether, the present results suggest the CBD disrupts the consolidation of different fear memories via anandamide-mediated activation of DH CB1 and CB2 receptors.
... Behavioral actions of eCBs found in cannabis include reductions in cortical activation (Chait and Perry, 1994;Heishman et al., 1997;Perez-Reyes et al., 1988) and injections of ANA in the brain stem induce slow wave sleep (SWS) and REM sleep (Murillo-Rodriguez et al., 1998), which suggest the possibility that the eCB system plays an endogenous role in LDT functioning. However, to the best of our knowledge, our pharmacological data, which showed that a CB1R antagonist exerts membrane actions on LDT cells, is the only evidence to date that indicates presence of an endogenous agent active at CB1Rs within the LDT (Soni et al., 2014;Soni and Kohlmeier 2016). ...
... The importance of the ECS in these synaptic processes suggests that endocannabinoids might play an important role in memory formation and processing. For example, AEA has been often regarded as strong modulator of acquisition phases (Murillo-Rodriguez, Sanchez-Alavez et al. 1998) and it is apparently involved in the modulation of memory consolidation and extinction (Luchicchi and Pistis 2012). The role of 2-AG in the regulation of mnemonic functions has also been investigated. ...
The endocannabinoid system (ECS) has been identified as the target of the main psychoactive component of the plant Cannabis sativa, Δ-9-tetrahydrocannabinol (THC). The ECS is composed of at least two receptors, the cannabinoid receptors 1 and 2, their endogenous ligands called endocannabinoids, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes involved in their synthesis and inactivation. CB1 is a seven-transmembrane G-protein-coupled receptor, and it is actually considered to be the most abundant metabotropic receptor in the brain. This chapter focuses on the behavioral processes regulated by (endo)cannabinoids acting through CB1 receptors, with special emphasis on memory, fear, and feeding behavior. The endogenous activation of the ECS is generally considered to occur in a very specific temporal and spatial frame. The impairment of memory performance is one of the effects associated with cannabis consumption in both humans and animals.
... Various neuromodulatory actions-as parts of sleep homeostasis-affect sleep and wakefulness via influencing the PPN. Intracerebroventricular administration or direct injection of cannabinoid agonists to the PPN increased REM sleep duration (Murillo-Rodríguez et al., 1998, 2008Murillo-Rodríguez, 2008) or non-REM sleep duration ( Bolla et al., 2008;Herrera-Solís et al., 2010). Injection of the muscarinic agonist carbachol to the PPN induced long-lasting REM-like states, as well as an increase in the amplitude and emergence probability of cortical gamma oscillations ( Kinney et al., 1998;Valencia et al., 2014). ...
Slow inward currents (SICs) are known as excitatory events of neurons caused by astrocytic glutamate release and consequential activation of neuronal extrasynaptic NMDA receptors. In the present article we investigate the role of these astrocyte-dependent excitatory events on a cholinergic nucleus of the reticular activating system (RAS), the pedunculopontine nucleus (PPN). It is well known about this and other elements of the RAS, that they do not only give rise to neuromodulatory innervation of several areas, but also targets neuromodulatory actions from other members of the RAS or factors providing the homeostatic drive for sleep. Using slice electrophysiology, optogenetics and morphological reconstruction, we revealed that SICs are present in a population of PPN neurons. The frequency of SICs recorded on PPN neurons was higher when the soma of the given neuron was close to an astrocytic soma. SICs do not appear simultaneously on neighboring neurons, thus it is unlikely that they synchronize neuronal activity in this structure. Occurrence of SICs is regulated by cannabinoid, muscarinic and serotonergic neuromodulatory mechanisms. In most cases, SICs occurred independently from tonic neuronal currents. SICs were affected by different neuromodulatory agents in a rather uniform way: if control SIC activity was low, the applied drugs increased it, but if SIC activity was increased in control, the same drugs lowered it. SICs of PPN neurons possibly represent a mechanism which elicits network-independent spikes on certain PPN neurons; forming an alternative, astrocyte-dependent pathway of neuromodulatory mechanisms.
An updated third edition of this award-winning book provides a comprehensive overview of the complex associations between cannabis and mental illness. Organised into easy to navigate sections, the book has been fully revised to feature eight entirely new chapters covering important novel aspects. Marijuana and Madness incorporates new research findings on the potential use of cannabinoids, and synthetic cannabinoids, in an array of mental illnesses, balanced against the potential adverse effects. The associations between cannabis and psychosis, developing putative models of 'cannabis induced' psychosis and pathways to schizophrenia are all covered. The book importantly discusses the impact of exposure to cannabis at various stages of neurodevelopment (in utero, in childhood, and during adolescence) and it thoroughly reviews the treatments for cannabis dependence and health policy implications of the availability of increasingly high potency cannabis. This book will quickly become an essential resource for all members of the mental health team.
Neurons express overlapping homeostatic mechanisms to regulate synaptic function and network properties in response to perturbations of neuronal activity. Endocannabinoids (eCBs) are bioactive lipids synthesized in the postsynaptic compartments to regulate synaptic transmission, plasticity, and neuronal excitability primarily through retrograde activation of presynaptic cannabinoid receptor type 1 (CB1). The eCB system is well situated to regulate neuronal network properties and coordinate presynaptic and postsynaptic activity. However, the role of the eCB system in homeostatic adaptations to neuronal hyperactivity is unknown. To address this issue, we used Western blotting and targeted lipidomics to measure adaptations in eCB system to bicuculline (BCC)-induced chronic hyperexcitation in mature cultured rat cortical neurons, and used multielectrode array (MEA) recording and live-cell imaging of glutamate dynamics to test the effects of pharmacological manipulations of eCB on network activities. We show that BCC-induced chronic hyperexcitation triggers homeostatic downscaling and a coordinated adaptation to enhance tonic eCB signaling. Hyperexcitation triggers first the downregulation of fatty acid amide hydrolase (FAAH), the lipase that degrades the eCB anandamide, then an accumulation of anandamide and related metabolites, and finally a delayed upregulation of surface and total CB1. Additionally, we show that BCC-induced downregulation of surface AMPA-type glutamate receptors (AMPARs) and upregulation of CB1 occur through independent mechanisms. Finally, we show that endocannabinoids support baseline network activities before and after downscaling and is engaged to suppress network activity during adaptation to hyperexcitation. We discuss the implications of our findings in the context of downscaling and homeostatic regulation of in vitro oscillatory network activities.
Drug development was historically started by targeting protein active sites as means to pharmacologically modulate the functional properties of the target. However, with high attrition rates, pharmacologists and medicinal chemists must begin thinking outside the box more earnestly when designing new drugs. Such thinking has created an impetus toward the discovery of “biased” or “allosteric” modulators to fine-tune activity, selecting for a desired therapeutic profile. This has become a sought-after approach for the therapeutic targeting of G protein-coupled receptors (GPCRs). Structure-based studies have greatly increased our mechanistic understanding of GPCR activation in large part due to the use of single domain antibodies (or nanobodies). Even if nanobodies were initially developed to assist in receptor stabilization for structure determination of GPCRs, they have now proven to be more than simple chaperones for crystallization. Nanobodies have helped elucidate key features of GPCR biological responses, as they also behave are allosteric regulators of GPCR pharmacology. For many years, optical biosensors relying on resonance energy transfer have conventionally been used to quantify allosteric regulation. Yet, the transformation of nanobodies into biosensors, sensing distinct receptor conformation or activation states, has generated unprecedented knowledge of GPCR biology and signal transduction. Further, peptidomimetic ligands or pepducins generated from the primary and secondary structures of GPCRs have also been used as key allosteric tools to understand and drive GPCR signaling. In this review, we discuss how intracellular allosteric modulators, such as intracellular ions, and tool compounds, such as pepducins and nanobodies, have informed our understanding of G protein-coupled receptors from structural studies, to the generation of receptor conformational and signaling signatures.
Type 1 and 2 cannabinoid receptors respond to endocannabinoids and contribute broadly to the function of the nervous system and immune system. Cannabinoid receptors participate in higher-order complex with other class A G protein-coupled receptors in both heterologous expression systems and native mammalian tissues. Receptor heteromers engage in protein-protein allosteric interactions that influence the conformation of receptor monomers within the complex. These altered conformations cause receptor heteromers to respond differently to cognate ligands compared to the individual receptors. This creates additional diversity in cell signaling that must be considered pharmacologically. In this chapter, we provide an overview of known cannabinoid receptor heteromers and signaling changes related to heteromer function. We also discuss the allosteric processes responsible for these effects and the therapeutic potential of this rapidly expanding group of receptor heteromers.
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.
Millions of Americans use cannabis for medical purposes including but not limited to pain, nausea, mood changes and appetite stimulation. The use of cannabinoid in the palliative care setting is a relatively new trend. Given the fact that a patient receiving palliative care is not necessarily approaching death, the increasing need for palliative care as the American population ages, this literature review was compiled in order to examine the potential efficacy of cannabis in treating the mental health comorbidities of palliative care patients. We attempted to create the most comprehensive report on cannabinoid use in palliative psychiatry. It summarizes the most recently published science on cannabinoid use in palliative care patients and its impact on mood and anxiety symptoms. The mechanism of action of cannabinoids on their associated receptors was elucidated, as were the pharmacological roles that specific molecules in cannabinoids, like cannabidiolic acid and terpenes, play in cannabinoids’ overall efficacy. The legal impediments to widespread cannabis use were also explored. While the potential efficacy of cannabinoids has proven to be mixed, more research is necessary to ensure that a potentially vital resource in treating palliative care patients does not go underutilized.
The role of medial septum in the genesis of slow-wave sleep and the inhibition of rapid eye movement sleep has been established using neurotoxic lesion and chemical stimulation of the medial septum. Intracerebroventricular injection of endocannabinoids (anandamide) decreases wake and increases slow-wave and rapid eye movement sleep in rats. Central cannabinoid (CB1) receptors are localized in the rat medial septum; however, the role of cannabinoid receptors at the medial septum on the regulation of sleep-wakefulness in rats lacks evidence. In this study, we have examined the changes in sleep architecture of 21 male Wistar rats, divided into three groups. Initially, 6 rats were used for dose standardization. Subsequently, one group (n=6) was microinjected with CB1 receptor agonist, R-(+)-WIN 55,212-2 mesylate salt, the second group (n=6) received microinjection of CB1 receptor antagonist LY 320135, and the third group (n=5) was microinjected with the vehicle, DMSO at the medial septum using stereotaxy. The sleep-wake cycle was recorded using electroencephalogram, electro-oculogram, and electromyogram. Microinjection of CB1 receptor agonist at the medial septum decreased slow-wave sleep and increased total sleep time. The increase in total sleep time was due to an increased percentage of rapid eye movement sleep. After the third and fourth hour of CB1 receptor antagonist microinjection at the medial septum, slow-wave sleep decreased when compared to vehicle injection, while rapid eye movement sleep decreased compared to baseline. We conclude that the endocannabinoid system at the septal nucleus acts through CB1 receptors to increase rapid eye movement sleep in rats.
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.
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.
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.
Despite the fact that the use of marihuana is illegal in most countries of the world, it still is one of the most commonly used drugs worldwide. 8.6% of the Mexican population, between 12-65 years old, has smoked marihuana at least once in their lifetime (2017). There has been a significant increase in the number of consumers in the last few years. Fatal cases associated with cannabis use had not been recognized for a long time, however, lately, deaths due to a cannabis hyperemesis syndrome (CHS) and deaths from self-mutilation have been reported. Although marihuana synthesizes several active substances with potential therapeutic properties, nowadays, the greatest use of marihuana in our country and in the world is recreational. This review discusses the consequences of using marihuana for recreational use, the social and health contexts regarding legalization and potential therapeutic uses of compounds isolated from the plant based on the scientific literature. Our contribution is to warn people about the potential negative impact on the health of recreational use marihuana and the urgency of supporting the research of its effects on the brain. Similarly, we aim to identify the active principles with potential therapeutic use.
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.
Most of the drugs of abuse affect the brain by interacting with naturally expressed molecular receptors. Marihuana affects a series of receptors including cannabinoid receptor 1 (CB1R) and CB2R, among others. Endogenous molecules with cannabinoid activity interact with these receptors naturally. Receptors, ligands, synthesizing and degrading enzymes, as well as transporters, have been described. This endocannabinoid system modulates behaviors and physiological processes, i.e. food intake, the sleep-waking cycle, learning and memory, motivation, and pain perception, among others. The rather broad distribution of endocannabinoids in the brain explains the different effects marihuana induces in its users. However, this very same anatomical and physiological distribution makes this system a useful target for therapeutic endeavors. In this review, we briefly discuss the potential of small molecules that target the endocannabinoids as therapeutic tools to improve behaviors and treat illnesses. We believe that under medical supervision, endocannabinoid targets offer new advantages for patients for controlling multiple medical disorders.
The endocannabinoid system (ECS) is an old and evolutionarily well preserved neurobiologic system controlling some key elements of organ homeostasis. In contrast to its long biologic history, the scientific record of the ECS is very short. Whereas the occurrence of genes for the endocannabinoid receptors has been described in ancient animals reaching at least as far back as the predecessor of tetrapods (amphibians reptiles, birds, and mammals), modern science has only more recently demonstrated that the ECS is involved in the regulation of a wide range of essential central and peripheral processes which include metabolism and feeding behavior, inflammatory- and anti-inflammatory immunologic reactions, neurobehavioral changes during stress and anxiety and the regulation of central functions such as cognition and memory. One of the most important roles of the ECS lies in the regulation and orchestration of the central and immunologic stress response to aversive and threatening life conditions. There are already data that the ECS is affected in humans during highly aversive conditions of parabolic flights and space flights as well as in other extreme living conditions (e.g. Antarctica). The ECS may therefore have an important function for adaption processes in such aversive conditions.
A survey of the literature indicates that both rapid eye movement sleep deprivation (RSD) and activation of cannabinoid CB1 receptor (CB1R) may impair novel object recognition (NOR) memory in rodents. To our knowledge, so far, no previous study has investigated the probable effects of RSD on the different phases of NOR memory. Moreover, far too little attention has been paid to the potential role of the CB1R in the effects of RSD on object memory. Therefore, the major objective of this study was to investigate the probable role of the CB1R in the acquisition, consolidation, retrieval, and reconsolidation of NOR memory in the RSD rats. A 12-h paradigm of RSD using the multiple platform method did not affect acquisition, but it impaired the consolidation, retrieval, and reconsolidation of NOR memory. Administration of the CB1R antagonist rimonabant (1 or 3 mg/kg, i.p.) did not have significant effects on the acquisition and reconsolidation, but it improved RSD-induced impairment of the consolidation and retrieval of object memory, especially at the dose of 3 mg/kg. In addition, the RSD paradigm did not affect the levels of plasma corticosterone as an important marker of stress in rat. The results revealed that RSD may have different effects on the different phases of NOR memory which may not be attributable to the effects of stress. Our findings would seem to suggest that the CB1R can be targeted to, at least partially, modulate the adverse effects of RSD on the process of NOR memory.
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).
Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the active component of Cannabis sativa preparations, such as hashish and marijuana, signals through cell surface receptors. Two types of cannabinoid receptors have been cloned and characterized. CB1 receptors are ubiquitously expressed in the neurons of the brain. They are presynaptically expressed in both inhibitory interneurons and excitatory neurons. CB2 receptors are expressed in microglial cells, astrocytes, and several neuron subpopulations. They are expressed in both the pre- and postsynaptic terminals. The present chapter discusses the current understanding of the cannabinoid receptors and their signaling cascades.
The limited efficiency of the current treatment options against the central nervous system (CNS) disorders has created increasing demands towards the development of novel theranostic strategies. The enormous research efforts in nanotechnology have led to the production of highly-advanced nanodevices and biomaterials in a variety of geometries and configurations for targeted delivery of genes, drugs, or growth factors across the blood-brain barrier. Meanwhile, the richness or reliability of data, drug delivery methods, therapeutic effects or potential toxicity of nanoparticles, occurrence of the unexpected phenomena due to the polydisperse or polymorphic nature of nanomaterials, and personalized theranostics have remained as challenging issues. In this respect, computational modelling has emerged as a powerful tool for rational design of nanoparticles with optimized characteristics including the selectivity, improved bioactivity, and reduced toxicity that might lead to the effective delivery of therapeutic agents. High-performance simulation techniques by shedding more light on the dynamical behaviour of neural networks and pathomechanisms of CNS disorders may provide imminent breakthroughs in nanomedicine. In the present review, the importance of integration of nanotechnology-based approaches with computational techniques for targeted delivery of theranostics to the CNS has been highlighted.
The plant Cannabis sativa, known as marijuana, is composed of more than 60 cannabinoids, which may have different effects on the sleep-wake cycle. The two main components of the plant are Δ⁹-tetrahydrocannabinol (THC), which is responsible for psychoactive effects, and cannabidiol (CBD), the main component of the plant that does not have psychological or behavioral effects. Other substances found in marijuana are: (1) cannabinol, which has a slightly less powerful effect than THC; (2) cannabigerol, a substance that is not as psychoactive as CBD; and (3) β-caryophyllene. The aim of this chapter is to describe the effects of cannabis and its components on the sleep-wake cycle.
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.
We report the isolation of a heretofore unrecognized brain lipid that is present in cerebrospinal fluid of sleep-deprived cats. The molecule appears to be a long-chain base structurally related to sphingosine and sphinganine in which a second unsaturated bond has been introduced. An increase in the degree of unsaturation of a key membrane component is expected to have important physiological consequences.
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.
Animal studies have recently demonstrated that increases in rapid eye movement (REM) sleep and actual number of rapid eye movements (REMs) over normal levels followed successful learning of an avoidance task. These increases persisted for many days following the end of the training sessions. It was hypothesized that similar extended increases in REM sleep parameters would follow an intensive learning task in humans. Senior college students were sleep monitored following the end of their Christmas examinations. Results showed that there was a significant increase in the number of REMs observed following the exams as compared to baseline and control subject values. The number of extra REMs was mot prominent during the fifth REM period of the night. A significantly increased REM density was observed at the fourth REM sleep period of the night. Results support the idea of REM sleep and/or the REMs themselves being involved in long-term memory processing several days after the end of training.
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.
Evidence is presented for a distinctive type of hippocampal synaptic modification [previously described for a molluscan gamma-aminobutyric acid (GABA) synapse after paired pre- and postsynaptic excitation]: transformation of GABA-mediated synaptic inhibition into synaptic excitation. This transformation persists with no further paired stimulation for 60 min or longer and is termed long-term transformation. Long-term transformation is shown to contribute to pairing-induced long-term potentiation but not to long-term potentiation induced by presynaptic stimulation alone. Further support for such mechanistic divergence is provided by pharmacologic effects on long-term transformation as well as these two forms of long-term potentiation by Cl- channel blockers, glutamate and GABA antagonists, as well as the endogenous cannabinoid ligand anandamide.
The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.
A molecule isolated from the cerebrospinal fluid of sleep-deprived cats has been chemically characterized and identified as
cis-9,10-octadecenoamide. Other fatty acid primary amides in addition to cis-9,10-octadecenoamide were identified as natural
constituents of the cerebrospinal fluid of cat, rat, and human, indicating that these compounds compose a distinct family
of brain lipids. Synthetic cis-9,10-octadecenoamide induced physiological sleep when injected into rats. Together, these results
suggest that fatty acid primary amides may represent a previously unrecognized class of biological signaling molecules.
We report the isolation of a heretofore unrecognized brain lipid that is present in cerebrospinal fluid of sleep-deprived cats. The molecule appears to be a long-chain base structurally related to sphingosine and sphinganine in which a second unsaturated bond has been introduced. An increase in the degree of unsaturation of a key membrane component is expected to have important physiological consequences.
Cognitive correlates of long-term cannabis use have been elusive. We tested the hypothesis that long-term cannabis use is associated with deficits in short term memory, working memory, and attention in a literate, westernized culture (Costa Rica) in which the effects of cannabis use can be isolated.
Two cohorts of long-term cannabis users and nonusers were studied. Within each cohort, users and nonusers were comparable in age and socioeconomic status. Polydrug users and users who tested positive for the use of cannabis at the time of cognitive assessment after a 72-hour abstention period were excluded. The older cohort (whose age was approximately 45 years) had consumed cannabis for an average of 34 years, and comprised 17 users and 30 nonusers, who had been recruited in San José, Costa Rica, and had been observed since 1973. The younger cohort (whose age was approximately 28 years) had consumed cannabis for an average of 8 years, and comprised 37 users and 49 nonusers. Short-term memory, working memory, and attentional skills were measured in each subject.
Older long-term users performed worse than older nonusers on 2 short-term memory tests involving learning lists of words. In addition, older long-term users performed worse than older nonusers on selective and divided attention tasks associated with working memory. No notable differences were apparent between younger users and nonusers.
Long-term cannabis use was associated with disruption of short-term memory, working memory, and attentional skills in older long-term cannabis users.
Five volunteers slept 8 to 15 consecutive nights in the laboratory with electroencephalogram, chin electromyogram, and eye movements monitored by the method originated by Dement and Kleitman. d9-tetrahydrocannabinol (THC), 20 mg administered at bedtime decreased the amount of time spent in the REM or paradoxical phase of sleep. Abrupt withdrawal of THC after 4 to 6 consecutive nights of use produced a mild insomnia characterized by difficulty in falling and staying asleep but did not produce a marked REM rebound.
Cannabinoids have been demonstrated to be effective antinociceptive agents when given intravenously. In order to determine whether spinal antinociception can be achieved while minimizing psychotomimetic properties, the pharmacological activity of delta 9-tetrahydrocannabinol (THC) was evaluated after intrathecal injection in male ICR mice. Although delta 9-THC produced potent antinociception, it also caused hypoactivity, hypothermia, and catalepsy. Intrathecal administration of delta 9-THC in mice which had their spinal cord transected at T12 also produced potent antinociception suggesting a spinal component to the antinociceptive effect. Biodispositional studies of [3H]delta 9-THC demonstrated that brain levels of the drug following intrathecal injection in spinally transected animals were not sufficient to produce the antinociceptive effect. These studies suggest the involvement of a spinal component in the antinociceptive action of the cannabinoids.
Although sleep-wake cycles are repeated every day and night and almost one-third of our lifetime is spent sleeping, the molecular mechanisms of sleep-wake regulation have remained little understood. Recent experimental evidence indicates that prostaglandins (PG) D2 and E2 are probably two of the major endogenous sleep-regulating substances, one promoting sleep and the other wakefulness, in rats, dogs, rabbits, monkeys, and probably in humans as well. Preliminary evidence indicates that the sites of action of PGD2 and E2 are located in the sleep and wake centers in or near the preoptic area and posterior hypothalamus, respectively.
The determination and characterization of a cannabinoid receptor from brain are reported. A biologically active bicyclic cannabinoid analgetic CP-55,940 was tritium-labeled to high specific activity. Conditions for binding to rat brain P2 membranes and synaptosomes were established. The pH optimum was between 7 and 8, and specific binding could be eliminated by heating the membranes to 60 degrees. Binding to the P2 membranes was linear within the range of 10 to 50 micrograms of protein/ml. Specific binding (defined as total binding displaced by 1 microM delta 9-tetrahydrocannabinol (delta 9-THC) or 100 nM desacetyllevonantradol) was saturable. The Kd determined from Scatchard analysis was 133 pM, and the Bmax for rat cortical P2 membranes was 1.85 pmol/mg of protein. The Hill coefficient for [3H]CP-55,940 approximated 1, indicating that, under the conditions of assay, a single class of binding sites was determined that did not exhibit cooperativity. The binding was rapid (kon approximately 2.6 x 10(-4) pM-1 min-1) and reversible (Koff approximately 0.016 min-1) and (koff' greater than 0.06 min-1). The two Kd values estimated from the kinetic constants approximately 55 pM and exceeded 200 pM, respectively. The binding of the agonist ligand [3H]CP-55,940 was decreased by the nonhydrolyzable GTP analog guanylylimidodiphosphate. The guanine nucleotide induced a more rapid dissociation of the ligand from the binding site, consistent with an allosteric regulation of the putative receptor by a G protein. The binding was also sensitive to MgCl2 and CaCl2. Binding of [3H]CP-55,940 was displaced by cannabinoid drugs in the following order of potency: CP-55,940 greater than or equal to desacetyllevonantradol greater than 11-OH-delta 9-THC = delta 9-THC greater than cannabinol. Cannabidiol and cannabigerol displaced [3H]CP-55,940 by less than 50% at 1 microM concentrations. The (-)-isomer of CP-55,940 displaced with 50-fold greater potency than the (+)-isomer. This pharmacology is comparable to both the inhibition of adenylate cyclase in vitro and the analgetic activity of these compounds in vivo. The criteria for a high affinity, stereoselective, pharmacologically distinct cannabinoid receptor in brain tissue have been fulfilled.
Marijuana seems firmly established as another social drug in Western countries, regardless of its current legal status. Patterns of use vary widely. As with other social drugs, the pattern of use is critical in determining adverse effects on health. Perhaps the major area of concern about marijuana use is among the very young. Using any drug on a regular basis that alters reality may be detrimental to the psychosocial maturation of young persons. Chronic use of marijuana may stunt the emotional growth of youngsters. Evidence for an amotivational syndrome is largely based on clinical reports; whether marijuana use is a cause or effect is uncertain. A marijuana psychosis, long rumored, has been difficult to prove. No one doubts that marijuana use may aggravate existing psychoses or other severe emotional disorders. Brain damage has not been proved. Physical dependence is rarely encountered in the usual patterns of social use, despite some degree of tolerance that may develop. The endocrine effects of the drug might be expected to delay puberty in prepubertal boys, but actual instances have been rare. As with any material that is smoked, chronic smoking of marijuana will produce bronchitis; emphysema or lung cancer have not yet been documented. Cardiovascular effects of the drug are harmful to those with preexisting heart disease; fortunately the number of users with such conditions is minimal. Fears that the drug might accumulate in the body to the point of toxicity have been groundless. The potential deleterious effects of marijuana use on driving ability seem to be self-evident; proof of such impairment has been more difficult. The drug is probably harmful when taken during pregnancy, but the risk is uncertain. One would be prudent to avoid marijuana during pregnancy, just as one would do with most other drugs not essential to life or well-being. No clinical consequences have been noted from the effects of the drug on immune response, chromosomes, or cell metabolites. Contamination of marijuana by spraying with defoliants has created the clearest danger to health; such attempts to control production should be abandoned. Therapeutic uses for marijuana, THC, or cannabinoid homologs are being actively explored. Only the synthetic homolog, nabilone, has been approved for use to control nausea and vomiting associated with cancer chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)
Arachidonic acid is a putative messenger in synaptic transmission which presumably plays a role in learning and memory. Previous experiments showed that inhibitors of phospholipase A2-dependent release of arachidonic acid cause amnesia in a one-trial passive avoidance task in the chick. To test if arachidonic acid is metabolized to other messengers, the effects of inhibitors of enzymes which metabolize arachidonic acid were tested in the same task. The cyclooxygenase inhibitors indomethacin, naproxen and ibuprofen caused amnestic effects at all concentrations tested when injected intracerebrally before training. Injections were 5 microliters of 5-20 mmolar solutions per hemisphere. The onset of amnestic effects was always 2 h after training, independently of drug type, concentration, and injection time before training. The delay of 2 h after training suggests that the drugs prevent induction of cyclooxygenase synthesis. Post-training injections had no effect. Control tests showed little effect of the drugs on motor control and motivation. Caffeic acid and esculetin, inhibitors of lipoxygenases, and sodium furegrelate, a thromboxane synthase inhibitor, had no effect on performance of chicks in the task at all concentrations or time points tested. The results indicate that cyclooxygenase products, but not lipoxygenase or thromboxane synthase products, play a role in memory consolidation in the chick when learning this task.
Two subtypes of cannabinoid receptors, CB1 and CB2, have been described to date, although future investigations may elucidate other receptors. The actions of cannabimimetic agents via CB1 receptors in brain are mediated by GI/O to inhibit adenylate cyclase and Ca2+ channels. Little is known about signal transduction mechanisms utilized by CB2 receptors. Three classes of agonist ligands regulate cannabinoid receptors: cannabinoid, aminoalkyl-indole, and eicosanoid derivatives. Cannabinoid receptors produce analgesia and modify cognition, memory, locomotor activity, and endocrine functions in mammals.
The purpose of the present study was to investigate the disruptive effects of cannabinoids on working memory as assessed in the eight-arm radial-maze. Systemic administration of delta 9-THC, WIN-55,212-2, and CP-55,940 increased the number of errors committed in the radial-maze. CP-55,940 was the most potent cannabinoid in impairing memory (ED50 = 0.13 mg/kg). delta 9-THC and WIN-55,212-2 disrupted maze-choice accuracy at equipotent doses (ED50 values = 2.1 and 2.2 mg/kg, respectively). In addition, systemic administration of each of these agents retarded completion time. Whereas the doses of delta 9-THC and CP-55,940 required to retard maze performance were higher than those needed to increase error numbers, WIN-55,212-2 was equipotent in both of these measures. On the other hand, neither anandamide, the putative endogenous cannabinoid ligand, nor cannabidiol, an inactive naturally occurring cannabinoid, had any apparent effects on memory. A second aim of this study was to elucidate the neuroanatomical substrates mediating the disruptive effects of cannabinoids on memory. Intrahippocampal injections of CP-55,940 impaired maze performance in a dose-dependent manner (ED50 = 8 micrograms/rat), but did not retard the amount of time required to complete the maze. The effects of intrahippocampal CP-55,940 were apparently specific to cognition because no other cannabinoid pharmacological effects (e.g., antinociception, hypothermia, and catalepsy) were detected. This dissociation between choice accuracy in the radial-maze and other cannabinoid pharmacological effects suggests that the working memory deficits produced by cannabinoids may be mediated by cannabinoid receptors in the hippocampus.
The antinociceptive effects of the putative endogenous cannabinoid ligand anandamide (ANA) and its fluorinated analog, fluoroanandamide (FA), were determined as measured by the tail-flick and p-phenylquinone (PPQ) stretch tests. The ED50 values (confidence limits) for ANA and FA were 77 (52-13) and 7 (2-21) micrograms/mouse, respectively, for the tail-flick test and 30 (23-41) and 0.5 (0.1-2) micrograms/mouse, respectively, for the PPQ test after intrathecal (i.t.) administration. ANA was not significantly less potent than delta 9-tetrahydrocannabinol (THC) in the tail-flick test, but it was less potent in the PPQ test. FA was more potent than either ANA or THC in tail-flick test. The antinociceptive effects of all drugs (administered i.t.) were blocked significantly or nearly abolished by the pretreatment of the mice with pertussis toxin (i.t.). Pretreatment of the mice with 5 and 25 micrograms forskolin per mouse or 10 micrograms 8-(4-chlorophenyl-thio)-adenosine-3',5'-monophosphate cyclic monosodium salt per mouse (both i.t.) significantly attenuated the antinociception produced by THC but not by ANA or FA. Various calcium modulators were tested in combination with THC, ANA, and FA, but they failed to alter the antinociceptive effects of the drugs. Various potassium channel blockers were tested in combination with the drugs. Apamin, a blocker of small (low)-conductance calcium-gated potassium channels that attenuates THC-induced antinociception, failed to alter ANA- or FA-induced antinociception. In contrast to THC, which is blocked by the kappa antagonist nor-binaltorphimine, ANA- and FA-induced antinociception was not altered by classic opioid antagonists. Also in contrast to THC, which enhances mu and delta opioid-induced antinociceptive effects, ANA failed to significantly alter opioid antinociception. ANA significantly shifted the THC dose-effect curve to the right. Thus, ED50 for DMSO/THC in the tail-flick test was shifted from 14 (7-29) to 54 (38-77) micrograms/mouse and was shifted in the hot-plate test from 22 (12-42) to 63 (43-92) micrograms/mouse. The magnitude of the shift in the ED50 was 3.8-fold in the tail-flick test and 2.9-fold in the hot-plate test. The shifts were parallel and significant. The Ki for the displacement of 3H-CP 55,940 binding by ANA and FA was 214 nM (+/- 45 S.E.M.) and 72 nM (+/- 5 S.E.M.), respectively, in pure spinal cord synaptosomes from the rat. ANA and FA were significantly cross-tolerant to THC. Although similarities between ANA and cannabinoids were shown, several marked differences were observed between ANA and the classic cannabinoids. ANA appears to function as both a cannabimimetic and a blocker of cannabinoid-induced antinociception.
We have reported that marihuana and its principal psycoactive compound, delta 9-tetrahydrocannabinol (delta 9-THC) produce alterations in several cerebral areas after acute treatment. Based on the involvement of 5-hydroxytryptamine (5-HT) on memory and learning and the reported effects of delta 9-THC on short-term memory, we designed an experiment to evaluate the memory performance and its possible relationship with serotonergic alterations after delta 9-THC administration. Male Wistar rats received an acute oral dose of THC (5 mg/kg). Short-Term memory was tested on a radial 8-arm maze with a 5 s delay, after 35 days of training. The animals were food deprived and adjusted for growth. 5-HT and its metabolite, 5-HIAA, levels were measured in cerebral cortex, dorsal hippocampus, ventral hippocampus, rostral neoestriatum and amygdala basal nucleus, by HPLC-ED. The experiment indicates an impairment of short-term memory in the radial maze test after delta 9-THC administration. The control group performed the test without errors, while the treated group made a significant number of errors (Z = 0.019, Mann-Whitney test). This behavioral effect did not seem to be related to serotonergic alterations, as the 5-HT turnover rate was not different between treated and control animals.
The effects of blocking phospholipase A2 (PLA2), a key enzyme in arachidonic acid (ArA) release, on memory retention have been studied in a one-trial passive avoidance task in the day-old chick. Bilateral intracerebral injections of the PLA2 and lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) (15 microliters of 4 mM NDGA/hemisphere, calculated to give an equivalent intracerebral concentration of 120 microM) or the PLA2 inhibitor aristolochic acid (AST) (5 microliters of a 4 mM AST/hemisphere, calculated to give an equivalent intracerebral concentration of approximately 40 microM) were made into the intermediate medial hyperstriatum ventrale (IMHV), an area that is of crucial importance for memory formation in the chick in this task. Pretraining injections of either inhibitor resulted in the chicks showing lasting amnesia for the avoidance response. The onset of amnesia with both inhibitors NDGA and AST was at 1.25 h post-training. Injection of drugs post-training had no effect on retention. Time and dose dependencies of both drugs were evaluated. Additional tests showed that the amnestic effect is not due to state-dependent learning nor to interference of the drugs with general motor ability or motivation. The results support the theory that arachidonic acid release is a necessary step in the early, although not immediate, events mediating the synaptic plasticity associated with memory formation. This is compatible with the hypothesis that ArA may serve as a late retrograde messenger between post- and presynaptic sites of plasticity, although it is not proof of such a role.
Anandamide (arachidonylethanolamide) is a brain constituent which binds to the cannabinoid receptor. We now report the first in vivo examination of this ligand. Anandamide administered i.p. in mice, caused lowering of activity in an immobility and in an open field test, and produced hypothermia and analgesia. These effects parallel those caused by psychotropic cannabinoids.
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.
In this article we summarize a wide variety of properties of arachidonic acid (AA) in the mammalian nervous system especially in the brain. AA serves as a biologically-active signaling molecule as well as an important component of membrane lipids. Esterified AA is liberated from the membrane by phospholipase activity which is stimulated by various signals such as neurotransmitter-mediated rise in intracellular Ca2+. AA exerts many biological actions which include modulation of the activities of protein kinases and ion channels, inhibition of neurotransmitter uptake, and enhancement of synaptic transmission. AA serves also as a precursor of a variety of eicosanoids, which are formed by oxidative metabolism of AA. AA cascade is activated under several pathological conditions in the brain such as ischemia and seizures, and may be involved in irreversible tissue damage. On the other hand, AA can show beneficial influences on brain tissues and cells in several situations. In a recent study using cultured brain neurons, we have found that AA shows quite distinct actions at a narrow concentration range, such as induction of cell death, promotion of cell survival and enhancement of neurite extension. The neurotoxic action is mediated by free radicals generated by AA metabolism, whereas the neurotrophic actions are exerted by AA itself. The observed in vitro actions of AA might be related to important roles of AA in brain pathogenesis and neural development.
Long-term depression (LTD) was studied in hippocampal slices from neonatal rats at the synapse between CA3 and CA1 pyramidal neurons. The induction of LTD requires the pairing of Ca2+ influx into the postsynaptic CA1 neuron through voltage-gated calcium channels with activation of metabotropic glutamate receptors. The expression of this LTD is at least partly presynaptic, implying the need for a retrograde messenger. We present evidence that arachidonic acid might serve such a function. Thus, arachidonic acid applications simulate LTD whereas blockade of arachidonic acid release inhibits LTD.
We have investigated the role of arachidonic acid, a putative retrograde messenger, in a one-trial aversive learning task in the day-old chick. The left and right intermediate medial hyperstriatum ventrale (IMHV) in the chick forebrain have previously been implicated in the formation of memory for this task. Using an ex vivo technique we have determined the concentrations of various fatty acids liberated from prisms prepared from these brain regions at different time points up to 24 h following passive avoidance training. At 30, 60, and 75 min posttraining the concentration of arachidonic acid, but not of other fatty acids, in prisms prepared from the left IMHV, but not the right IMHV, was enhanced compared with that in chicks trained on a nonaversive water-coated bead. To test whether arachidonic acid liberation from the left IMHV was receptor-stimulated we showed that (a) liberation of endogenous arachidonic acid from homogenate prepared from the left and right IMHV of untrained chicks was stimulated by depolarization with KCl (50 mM) and that (b) glutamate agonists of the NMDA and metabotropic subtypes of glutamate receptor stimulated release of preloaded [14C] arachidonic acid from prisms prepared from the left IMHV but not the right IMHV. These results indicate that arachidonic acid is liberated from the left IMHV following passive avoidance training in the day-old chick and may play a role as a retrograde messenger in this memory task.
Endogenous neuromodulatory molecules are commonly coupled to specific metabolic enzymes to ensure rapid signal inactivation. Thus, acetylcholine is hydrolysed by acetylcholine esterase and tryptamine neurotransmitters like serotonin are degraded by monoamine oxidases. Previously, we reported the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats. cis-9-Octadecenamide, or oleamide, has since been shown to affect serotonergic systems and block gap-junction communication in glial cells (our unpublished results). We also identified a membrane-bound enzyme activity that hydrolyses oleamide to its inactive acid, oleic acid. We now report the mechanism-based isolation, cloning and expression of this enzyme activity, originally named oleamide hydrolase, from rat liver plasma membranes. We also show that oleamide hydrolase converts anandamide, a fatty-acid amide identified as the endogenous ligand for the cannabinoid receptor, to arachidonic acid, indicating that oleamide hydrolase may serve as the general inactivating enzyme for a growing family of bioactive signalling molecules, the fatty-acid amides. Therefore we will hereafter refer to oleamide hydrolase as fatty-acid amide hydrolase, in recognition of the plurality of fatty-acid amides that the enzyme can accept as substrates.
Cerebrodiene (cis-9, 10-octadecenoamide) was recently isolated from cerebral fluid of sleep-deprived cats and shown to induce sleep in rats. Because this lipid amide is related to arachidonylethanolamide (AEA), and because AEA binds to the cannabinoid receptor with high affinity, we investigated the binding affinity of cerebrodiene and some analogs to the cannabinoid receptor. In addition, we tested the ability of these compounds to act as cannabinoid receptor agonists by determining GTP gamma S binding. Each of the analogs competed for [3H] CP55940 binding, but with relatively low affinity (Ki = 26-44 microM). These analogs were not able to stimulate binding of GTP gamma S at concentrations of 100 microM or 1 mM. We conclude that the sleep-inducing actions of cerebrodiene are not mediated via activation of the cannabinoid receptor.
1. The influence of voltage dependent calcium channel blocker (VDCC), nimodipine and N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 on the brain free arachidonic acid (FAA) level and on the learning ability in hypoxia-exposed rats was examined. 2. Some animals were decapitated after cerebral hypoxia had been obtained and the brain FAA level was determined by gas chromatography. The other animals were trained in a passive avoidance procedure and were exposed to hypoxic conditions immediately after the learning trial response had been acquired. A passive avoidance retention test was performed 24 hours later. 3. Various doses of nimodipine (0.03; 0.1; 0.3 and 1.0 mg/kg) and MK-801 (0.03; 0.1 and 0.3 mg/kg) had been injected 30 minutes before biochemical or behavioral procedures started. 4. It was found that hypoxia strongly increased the brain FAA level and impaired the retention of the passive avoidance response. 5. Pretreatment with 0.3 mg/kg and 1.0 mg/kg of nimodipine prevented the brain FAA accumulation. It has also been shown that all tested doses of nimodipine significantly improved the retention deficit in the animals exposed to hypoxia. 6. Neither the one of tested doses of MK-801 influenced significantly the increase of the brain FAA level and/or passive avoidance behavior in hypoxic animals. 7. These results confirm the hypothesis that the brain FAA accumulation and cognitive impairment, caused by hypoxia, are maybe associated with disturbances in calcium homeostasis and that nimodipine may be useful in ameliorating the hypoxia-induced brain tissue damage. Blocade of NMDA receptor-channel complex by MK-801 was not sufficient to prevent hypoxia-induced neuronal damage.
Cannabinoid receptors are molecular targets for marijuana and hashish, the widespread drugs of abuse. These receptors are expressed in areas of the central nervous system that contribute in important ways to the control of memory, cognition, movement and pain perception. Indeed, such functions can be strongly influenced by cannabinoid drugs, with consequences that include euphoria, analgesia, sedation and memory impairment. Although the pharmacology of cannabinoid drugs is now beginning to be understood, we still lack essential information on the endogenous signalling system(s) by which cannabinoid receptors are normally engaged. An endogenous ligand for cannabinoid receptors, anandamide, has been described. Here we report that sn-2 arachidonylglycerol (2-AG), a cannabinoid ligand isolated from intestinal tissue, is present in brain in amounts 170 times greater than anandamide. 2-AG is produced in hippocampal slices by stimulation of the Schaffer collaterals, an excitatory fibre tract that projects from CA3 to CA1 neurons. Formation of 2-AG is calcium dependent and is mediated by the enzymes phospholipase C and diacylglycerol lipase. 2-AG activates neuronal cannabinoid receptors as a full agonist, and prevents the induction of long-term potentiation at CA3-CA1 synapses. Our results indicate that 2-AG is a second endogenous cannabinoid ligand in the central nervous system.
The effect of 12 month feeding of 5% palm oil or sardine oil diet on the maze-learning ability, fatty acid composition of brain stem phospholipids and synaptic membrane fluidity in mice was studied. The time required to reach the maze exit and the number of times that a mouse strayed into blind alleys in the maze were measured three times every 4 days. The time and number of mice fed on the sardine oil diet were less than those of animals fed on the palm oil diet in the first and second trials. The results of fatty acid composition analysis of brain stem phosphatidylethanolamine showed that the percentage of docosahexaenoic acid (22:6, n-3; DHA) was higher, but the arachidonic acid (20:4, n-6; AA) and docosatetraenoic acid (22:4, n-6; DTA) were lower in the sardine oil diet fed-mice than in the palm oil diet fed-animals. Moreover, the microviscosity of the synaptic plasma membrane in the sardine oil diet group was lower than that in the palm oil diet group. These results suggest that the adult mice fed on the sardine oil diet for a long period maintain higher levels of docosahe xaenoic acid in brain phospholipids, synaptic membrane fluidity and maze-learning ability than animals fed on the palm oil diet.
Literature pertaining to the effects of cannabis use and health which has been published during the past 11 years has been reviewed. Many older concerns about adverse effects on health (chromosomal damage, ‘cannabinol psychosis’, endocrine abnormalities, cardiac events, impaired immunity) no longer seem to elicit much interest. Continuing concerns about the adverse cognitive effects of chronic use indicate that these can be demonstrated by proper testing; some studies suggest that they may be long-lasting. Although cannabis does not produce a specific psychosis, the possibility exists that it may exacerbate schizophrenia in persons predisposed to that disorder. However, evidence from retrospective surveys must always be questioned. Tolerance and dependence have occurred in man, confirming previous findings in many other species. Addiction tends to be mild and is probably less severe than with other social drugs. Driving under the influence of cannabis is impaired acutely; how long such impairments last is still unknown. More exacting tasks, such as flying an airplane, may be impaired for as long as 24 hours. While there is no doubt that marijuana smoke contains carcinogens, an increase in cancer among users has thus far been anecdotal. Because of the long latent period between cancer induction and initiation of cigarette smoking, the full story is yet to be told. Marijuana use during pregnancy is not advised although the consequences are usually not greater than those of smoking cigarettes, and far less than those from alcohol use.
Whether smoked marijuana should become a therapeutic agent requires a cost-benefit analysis of the potential benefits versus the adverse effects of such use as we now know them.
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