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Intrahypothalamic injection of cannabidiol increases the extracellular levels of adenosine in nucleus accumbens in rats
Abstract
Cannabidiol (CBD) is a constituent of Cannabis sativa that promotes wakefulness as well as enhances endogenous levels of wake-related neurotransmitters, including dopamine. However, at this date, the effects of CBD on the sleep-inducing molecules, such as adenosine (AD), are unknown. Here, we report that intrahypothalamic injection of CBD (10μg/1μL) increases the extracellular levels of AD collected from nucleus accumbens. Furthermore, the pharmacodynamic of this drug shows that effects on the contents of AD last 2h post-injection. These preliminary findings suggest that CBD promotes the endogenous accumulation of AD.
... Previous results have shown the role of the nucleus accumbens (AcbC) in the sleep-wake cycle modulation (Qiu et al., 2012). Moreover, studies from our group have demonstrated reliable measurements of sleep-related neurochemicals such as dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT), of samples collected from AcbC (Mijangos-Moreno et al., 2014Murillo-Rodríguez et al., 2017). Thus, we determined whether DZNep or GSK-J1 might exert changes in the levels of these neurochemicals as characterized from microdialysis samples collected from AcbC. ...
... Artificial cerebrospinal fluid (aCSF [composition: NaCl 147 mM, KCl 3 mM, CaCl 1.2 mM, MgCl 1.0 mM, pH 7.2]) was perfused through a miniature tube (0.65 mm OD × 0.12 mm ID; BAS, West Lafayette, IN, United States) attached to a 2.5 mL syringe (BAS, West Lafayette, IN, United States) with a pump (flow rate: 0.25 µL/min; BAS Bee, West Lafayette, IN, United States). As standardized procedure, before the beginning of the experiments, in all rats, the microdialysis membrane was stabilized during 24 h and samples from that period were excluded for the final analysis as suggested from previous reports (Mijangos-Moreno et al., 2014Murillo-Rodríguez et al., 2017). Right after the period of stabilization of membrane was covered, experimental trials were given and animals were reattached to the microdialysis system. ...
... Later, all samples were stored (−80 • C) for further analysis. The microdialysis sampling procedure was developed as previous reports (Mijangos-Moreno et al., 2014Murillo-Rodríguez et al., 2017). ...
Histone methylation/demethylation plays an important modulatory role in chromatin restructuring, RNA transcription and is essential for controlling a plethora of biological processes. Due to many human diseases have been related to histone methylation/demethylation, several compounds such as 3-deazaneplanocin A (DZNep) or 3-((6-(4,5-Dihydro-1H-benzo[d]azepin-3(2H)-yl)-2-(pyridin-2-yl)pyrimidin-4-yl)amino)propanoic acid; N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-β-Alanine (GSK-J1), have been designed to inhibit histone methylase or suppress histone demethylase, respectively. In the present study, we investigated the effects on the sleep-wake cycle and sleep-related neurochemical levels after systemic injections of DZNep or GSK-J1 given during the light or dark phase in rats. DZNep dose-dependently (0.1, 1.0, or 10 mg/kg, i.p.) prolonged wakefulness (W) duration while decreased slow wave sleep (SWS) and rapid eye movement sleep (REMS) time spent during the lights-on period with no changes observed in dark phase. In opposite direction, GSK-J1 (0.1, 1.0, or 10 mg/kg, i.p.) injected at the beginning of the lights-on period induced no statistical changes in W, SWS, or REMS whereas if administered at darkness, we found a diminution in W and an enhancement in SWS and REMS. Finally, brain microdialysis experiments in freely moving animals were used to evaluate the effects of DZNep or GSK-J1 treatments on contents of sleep-related neurochemicals. The results showed that DZNep boosted extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, adenosine, and acetylcholine if injected at the beginning of the lights-on period whereas GSK-J1 exerted similar outcomes but when administered at darkness. In summary, DZNep and GSK-J1 may control the sleep-wake cycle and sleep-related neurochemicals through histone methylation/demethylation activity.
... In this regard, our laboratory reported that administrations of CBD in rats during the lights-on period increased wakefulness, but decreased sleep [20][21][22]. Remarkably, the effects of CBD on sleep has been found after systemic or central injections, as well as posterior to intracerebral perfusion [20][21][22]24]. Moreover, CBD also caused a significant enhancement of the extracellular levels of dopamine (DA) collected from nucleus accumbens [20][21][22]. ...
... Altogether, the data suggest that CBD induces alertness by increasing contents of DA. However, later reports have indicated that CBD also modifies the levels of other wake-related compounds, such as adenosine [24] as well as monoamines [25,26]. Thus, while it seems that CBD exerts effects on adenosine and monoamines contents, it is not clear whether this cannabinoid might also affect an additional neurochemical related to wakefulness, such as acetylcholine (ACh). ...
... We and others have previously reported that treatment with CBD modifies wake-related neurochemical levels [24,26,35,36]. However, there is no data available regarding whether CBD administration might exert effects in additional wake-related neurochemicals, such as ACh. ...
Cannabis sativa is a plant that contains more than 500 components, of which the most studied are Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Several studies have indicated that CBD displays neurobiological effects, including wake promotion. Moreover, experimental evidence has shown that injections of CBD enhance wake-related compounds, such as monoamines (dopamine, serotonin, epinephrine, and norepinephrine). However, no clear evidence is available regarding the effects of CBD on additional wake-related neurochemicals such as acetylcholine (ACh). Here, we demonstrate that systemic injections of CBD (0, 5, 10 or 30 mg/kg, i.p.) at the beginning of the lights-on period, increase the extracellular levels of ACh collected from the basal forebrain and measured by microdialysis and HPLC means. Moreover, the time course effects on the contents of ACh were present 5 h post-injection of CBD. Altogether, these data demonstrate that CBD increases ACh levels in a brain region related to wake control. This study is the first to show the effects of ACh levels in CBD-treated rats and suggests that the basal forebrain might be a site of action of CBD for wakefulness modulation.
... Experiments have demonstrated the critical role of nucleus accumbens (AcbC) in sleep control (Lazarus et al., 2012(Lazarus et al., , 2013Qiu et al., 2012;Zhang et al., 2013;Liu et al., 2016). Moreover, previous work from our laboratory has provided reliable measurements of monoamines and AD from AcbC Mijangos-Moreno et al., 2014. Thus, these previous evidence allowed us to consider AcbC as candidate for microdialysis sampling. ...
... To obtain the recovery rate, data were calculated as follows: Recovery rate (%) = (the peak area ratio of the sample from microdialysis sample)/(the peak area ratio of the sample in the test solution). Further details of microdialysis procedures are available in previous reports (Porkka-Heiskanen et al., 2000;Blanco-Centurion et al., 2006;Murillo-Rodrı´guez et al., 2007, 2011Mijangos-Moreno et al., 2014. ...
... Japan). All procedures for detection and measurement of monoamines or AD were developed according to previous reports Mijangos-Moreno et al., 2014. ...
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.
... mm, with reference to Bregma [Paxinos and Watson, 2005]). The entire surgical procedure was developed according to previous reports Mijangos-Moreno et al., 2014). Upon completion of the surgical procedures, the rats were connected to the sleep-recording system for the post-operative recovery period (7 days). ...
... After the surgery, the rats were placed in the microdialysis bowls for recovery and habituation to the experimental conditions during 7 days. The microdialysis procedure was developed according to previous reports (Mijangos- Moreno et al., 2014). Briefly, a week after the surgery and 24 h before the experiment, the microdialysis stylet was removed from guide-cannula and probe (1 mm . ...
... The dialysates were injected into the high performance liquid chromatography (HPLC) for detection and quantification of the contents of DA, 5-HT, NE and AD. The settings and procedures for the analysis of monoamines using the HPLC were carried out as previously published whereas AD measurement was determined as described elsewhere (Mijangos- Moreno et al., 2014). ...
... mm, with reference to Bregma [Paxinos and Watson, 2005]). The entire surgical procedure was developed according to previous reports Mijangos-Moreno et al., 2014). Upon completion of the surgical procedures, the rats were connected to the sleep-recording system for the post-operative recovery period (7 days). ...
... After the surgery, the rats were placed in the microdialysis bowls for recovery and habituation to the experimental conditions during 7 days. The microdialysis procedure was developed according to previous reports (Mijangos- Moreno et al., 2014). Briefly, a week after the surgery and 24 h before the experiment, the microdialysis stylet was removed from guide-cannula and probe (1 mm . ...
... The dialysates were injected into the high performance liquid chromatography (HPLC) for detection and quantification of the contents of DA, 5-HT, NE and AD. The settings and procedures for the analysis of monoamines using the HPLC were carried out as previously published whereas AD measurement was determined as described elsewhere (Mijangos- Moreno et al., 2014). ...
The peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear protein that plays an essential role in diverse neurobiological processes. However, the role of PPARα on the sleep modulation is unknown. Here, rats treated with an intrahypothalamic injection of Wy14643 (10μg/1μL; PPARα agonist) enhanced wakefulness and decreased slow wave sleep and rapid eye movement sleep whereas MK-886 (10μg/1μL; PPARα antagonist) promoted opposite effects. Moreover, Wy14643 increased dopamine, norepinephrine, serotonin, and adenosine contents collected from nucleus accumbens. The levels of these neurochemicals were diminished after MK-886 treatment. The current findings suggest that PPARα may participate in the sleep and neurochemical modulation.
... Additionally, the authors suggested that this relationship may be crucial in the sleep promoting effects of CBD. 102 CBD also affects the activity of intracellular transporters of endocannabinoids such as fatty acid binding proteins 1, 3, 5, and 7. [102][103][104] There are reports of modulation of the activity of transporters of multidrug resistance proteins (multidrug resistance-associated protein 1 (ABCC1), ATP-binding cassette super-family G member 2 (ABCG2) or P-glycoprotein). However, this occurred at high concentrations of the substance, suggesting a lack of physiological relevance of this phenomenon. ...
... Additionally, the authors suggested that this relationship may be crucial in the sleep promoting effects of CBD. 102 CBD also affects the activity of intracellular transporters of endocannabinoids such as fatty acid binding proteins 1, 3, 5, and 7. [102][103][104] There are reports of modulation of the activity of transporters of multidrug resistance proteins (multidrug resistance-associated protein 1 (ABCC1), ATP-binding cassette super-family G member 2 (ABCG2) or P-glycoprotein). However, this occurred at high concentrations of the substance, suggesting a lack of physiological relevance of this phenomenon. ...
Background:
Cannabis, more commonly known as marijuana or hemp, has been used for centuries to treat various conditions. Cannabis contains two main components cannabidiol (CBD) and tetrahydrocannabinol (THC). CBD, unlike THC, is devoid of psychoactive effects and is well tolerated by the human body but has no direct effect on the receptors of the endocannabid system, despite the lack of action on the receptors of the endocannabid system.
Objectives and methods:
We have prepared a literature review based on the latest available literature regarding the analgesic effects of CBD. CBD has a wide range of effects on the human body. In this study, we will present the potential mechanisms responsible for the analgesic effect of CBD. To the best of our knowledge, this is the first review to explore the analgesic mechanisms of CBD.
Results and conclusion:
The analgesic effect of CBD is complex and still being researched. CBD models the perception of pain by acting on G protein-coupled receptors. Another group of receptors that CBD acts on are serotonergic receptors. The effect of CBD on an enzyme of potential importance in the production of inflammatory factors such as cyclooxygenases and lipoxygenases has also been confirmed. The presented potential mechanisms of CBD's analgesic effect are currently being extensively studied.
... The anti-epileptic drug cannabidiol, a putative ENT1 inhibitor [23,[36][37][38][39], had no effect on body temperature and did not augment adenosine-induced hypothermia at 10 mg/kg, i.p. (Fig. S1). ...
... CBD is reported to be a sub-micromolar ENT1 inhibitor [23,[36][37][38], but CBD did not enhance adenosine-induced hypothermia. Thus, CBD does not appear to be sufficiently efficacious as an ENT1 inhibitor under the in vivo conditions tested. ...
Some non-adenosinergic drugs are reported to also act through adenosine receptors (ARs). We used mouse hypothermia, which can be induced by agonism at any of the four ARs, as an in vivo screen for adenosinergic effects. An AR contribution was identified when a drug caused hypothermia in wild type mice that was diminished in mice lacking all four ARs (quadruple knockout, QKO). Alternatively, an adenosinergic effect was identified if a drug potentiated adenosine-induced hypothermia. Four drugs (dipyridamole, nimodipine, cilostazol, cyclosporin A) increased the hypothermia caused by adenosine. Dipyridamole and nimodipine probably achieved this by inhibition of adenosine clearance via ENT1. Two drugs (cannabidiol, canrenoate) did not cause hypothermia in wild type mice. Four other drugs (nifedipine, ranolazine, ketamine, ethanol) caused hypothermia, but the hypothermia was unchanged in QKO mice indicating non-adenosinergic mechanisms. Zinc chloride caused hypothermia and hypoactivity; the hypoactivity was blunted in the QKO mice. Interestingly, the antidepressant amitriptyline caused hypothermia in wild type mice that was amplified in the QKO mice. Thus, we have identified adenosine-related effects for some drugs, while other candidates do not affect adenosine signaling by this in vivo assay. The adenosine-modulating drugs could be considered for repurposing based on predicted effects on AR activation.
... Interestingly, there is a large number of studies reporting the conflicting effects of cannabidiol (CBD) on sleep-wake cycle. It has been reported that CBD, a constituent of Cannabis sativa, promotes wakefulness and increases endogenous levels of wake-related neurotransmitters including dopamine [88]. However, previous study has demonstrated that CBD promotes sleep in rats [89]. ...
... Human studies have shown that dosage of 70 mg/day of cannabinoids enhances sleep [95,96]. Previous research has revealed that CBD increases the accumulation of adenosine, a sleep-inducing factor [88]. Another study has reported that i.p. injection of CBD increases sleep in rats [89]. ...
Cannabis sativa (Marijuana) has a long history as a medicinal plant and Δ9-tetrahydrocannabinol (Δ9-THC) is the most active component in this plant. Cannabinoids are interesting compounds with various modulatory effects on physiological processes and cognitive functions. The use of cannabinoids is a double-edged sword, because they induce both adverse and therapeutic properties. One of the most important roles of cannabinoids is modulating sleep-wake cycle. Sleep, its cycle, and its mechanism are highly unknown. Also, the effects of cannabinoids on sleep-wake cycle are so inconsistent. Thus, understanding the role of cannabinoids in modulating sleep-wake cycle is a critical scientific goal. Cannabinoids interact with many neurotransmitter systems. In this review article, we chose serotonin due to its important role in regulating sleep-wake cycle. We found that the interaction between cannabinoids and serotonergic signaling especially in the dorsal raphe is extensive, unknown, and controversial.
... Prior findings have demonstrated that systemic and central administrations of CBD increase alertness. However, it is worthy to mention that these studies were developed in adult animals and under acute pharmacological experimental trials (Murillo-Rodríguez et al. 2006, 2011Mijangos-Moreno et al. 2014). Clearly, these data provide great significance for public health in regard to the long-term effects of CBD in adulthood if they are relevant to chronic uses in adolescents. ...
... Given that CBD apparently does not induce negative outcomes in multiple neurobiological systems and, unlike Δ 9 -THC, shows effective response for managing medical issues such as psychosis, inflammation, and anxiety, among several pathological conditions, it has attracted pharmacological and pharmaceutical attention (Schrot and Hubbard 2016;Verrotti et al. 2016;Grof 2018;Russo 2018;Bloomfield et al. 2019). Despite these interesting results, it is worthy to highlight that since CBD induces a wider range of proven effectiveness involving non-endocannabinoid signaling systems, including cholinergic, adenosinergic, monoaminergic, serotonergic, and glycinergic systems (Murillo-Rodríguez et al. 2011Ibeas Bih et al. 2015;Mijangos-Moreno et al. 2014), it is not yet known which of these mechanisms might be responsible for the presumably therapeutic properties of CBD. Moreover, the likely engagement of multiple biological pathways activated by CBD could be associated with long-term unknown neurobiological failures. ...
RationaleThe medical uses of cannabidiol (CBD), a constituent of the Cannabis sativa, have accelerated the legal and social acceptance for CBD-based medications but has also given the momentum for questioning whether the long-term use of CBD during the early years of life may induce adverse neurobiological effects in adulthood, including sleep disturbances. Given the critical window for neuroplasticity and neuro-functional changes that occur during stages of adolescence, we hypothesized that CBD might influence the sleep-wake cycle in adult rats after their exposure to CBD during the adolescence.Objectives
Here, we investigated the effects upon behavior and neural activity in adulthood after long-term administrations of CBD in juvenile rats.Methods
We pre-treated juvenile rats with CBD (5 or 30 mg/Kg, daily) from post-natal day (PND) 30 and during 2 weeks. Following the treatments, the sleep-wake cycle and NeuN expression was analyzed at PND 80.ResultsWe found that systemic injections of CBD (5 or 30 mg/Kg, i.p.) given to adolescent rats (post-natal day 30) for 14 days increased in adulthood the wakefulness and decreased rapid eye movement sleep during the lights-on period whereas across the lights-off period, wakefulness was diminished and slow wave sleep was enhanced. In addition, we found that adult animals that received CBD during the adolescence displayed disruptions in sleep rebound period after total sleep deprivation. Finally, we determined how the chronic administrations of CBD during the adolescence affected in the adulthood the NeuN expression in the suprachiasmatic nucleus, a sleep-related brain region.Conclusions
Our findings are relevant for interpreting results of adult rats that were chronically exposed to CBD during the adolescence and provide new insights into how CBD may impact the sleep-wake cycle and neuronal activity during developmental stages.
... While the precise neuroanatomical regions responsible for CBD's actions are not known, considerable evidence implicates the nucleus accumbens (NAc) as an important site for CBD's modulatory effects on various cognitive and behavioral phenomena (Guimarães et al, 2004;Bhattacharyya et al, 2009;Valvassori et al, 2011;Mijangos-Moreno et al, 2014;Pedrazzi et al, 2015). For example, CBD attenuates THCinduced dysregulation of the ventral striatum during verbal recall tasks (Bhattacharyya et al, 2009) and increases c-fos and adenosine levels in rodent NAc (Guimarães et al, 2004;Mijangos-Moreno et al, 2014). ...
... While the precise neuroanatomical regions responsible for CBD's actions are not known, considerable evidence implicates the nucleus accumbens (NAc) as an important site for CBD's modulatory effects on various cognitive and behavioral phenomena (Guimarães et al, 2004;Bhattacharyya et al, 2009;Valvassori et al, 2011;Mijangos-Moreno et al, 2014;Pedrazzi et al, 2015). For example, CBD attenuates THCinduced dysregulation of the ventral striatum during verbal recall tasks (Bhattacharyya et al, 2009) and increases c-fos and adenosine levels in rodent NAc (Guimarães et al, 2004;Mijangos-Moreno et al, 2014). In addition, CBD blocks amphetamine-induced oxidative stress in the NAc (Valvassori et al, 2011) and intra-NAc CBD attenuates amphetamineinduced deficits in prepulse inhibition (Pedrazzi et al, 2015;Renard et al, 2016b). ...
Emerging evidence suggests that the largest phytochemical component of cannabis, cannabidiol (CBD), may possess pharmacotherapeutic properties in the treatment of neuropsychiatric disorders. CBD has been reported to functionally interact with both the mesolimbic dopamine (DA) and serotonergic (5-HT) receptor systems. However, the underlying mechanisms by which CBD may modulate emotional processing are not currently understood. Using a combination of in vivo electrophysiological recording and fear conditioning in rats, the present study aimed to characterize the behavioral, neuroanatomical, and pharmacological effects of CBD within the mesolimbic pathway, and its possible functional interactions with 5-HT and DAergic transmission. Using targeted microinfusions of CBD into the shell region of the mesolimbic nucleus accumbens (NASh), we report that intra-NASh CBD potently blocks the formation of conditioned freezing behaviors. These effects were challenged with DAergic, cannabinoid CB1 receptor, and serotonergic (5-HT 1A) transmission blockade, but only 5-HT 1A blockade restored associative conditioned freezing behaviors. In vivo intra-ventral tegmental area (VTA) electrophysiological recordings revealed that behaviorally effective doses of intra-NASh CBD elicited a predominant decrease in spontaneous DAergic neuronal frequency and bursting activity. These neuronal effects were reversed by simultaneous blockade of 5-HT 1A receptor transmission. Finally, using a functional contralateral disconnection procedure, we demonstrated that the ability of intra-NASh CBD to block the formation of conditioned freezing behaviors was dependent on intra-VTA GABAergic transmission substrates. Our findings demonstrate a novel NAc → VTA circuit responsible for the behavioral and neuronal effects of CBD within the mesolimbic system via functional interactions with serotonergic 5-HT 1A receptor signaling.
... West Lafayette, IN, United States) for recovery as well as habituation for the experimental conditions across 7 days. All surgical procedures of microdialysis probes were accomplished as previously reported (Murillo-Rodríguez et al., 2007a;Mijangos-Moreno et al., 2014). ...
... For obtaining the recovery rate, data were calculated as follows: Recovery rate (%) = (the peak area ratio of the sample from microdialysis sample)/(the peak area ratio of the sample in the test solution). The whole microdialysis procedures were carried out as previous reports (Porkka-Heiskanen et al., 2000;Blanco-Centurion et al., 2006;Mijangos-Moreno et al., 2014Murillo-Rodríguez et al., 2016). ...
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.
... While the precise neuroanatomical regions responsible for CBD's actions are not known, considerable evidence implicates the nucleus accumbens (NAc) as an important site for CBD's modulatory effects on various cognitive and behavioral phenomena (Guimarães et al, 2004;Bhattacharyya et al, 2009;Valvassori et al, 2011;Mijangos-Moreno et al, 2014;Pedrazzi et al, 2015). For example, CBD attenuates THCinduced dysregulation of the ventral striatum during verbal recall tasks (Bhattacharyya et al, 2009) and increases c-fos and adenosine levels in rodent NAc (Guimarães et al, 2004;Mijangos-Moreno et al, 2014). ...
... While the precise neuroanatomical regions responsible for CBD's actions are not known, considerable evidence implicates the nucleus accumbens (NAc) as an important site for CBD's modulatory effects on various cognitive and behavioral phenomena (Guimarães et al, 2004;Bhattacharyya et al, 2009;Valvassori et al, 2011;Mijangos-Moreno et al, 2014;Pedrazzi et al, 2015). For example, CBD attenuates THCinduced dysregulation of the ventral striatum during verbal recall tasks (Bhattacharyya et al, 2009) and increases c-fos and adenosine levels in rodent NAc (Guimarães et al, 2004;Mijangos-Moreno et al, 2014). In addition, CBD blocks amphetamine-induced oxidative stress in the NAc (Valvassori et al, 2011) and intra-NAc CBD attenuates amphetamineinduced deficits in prepulse inhibition (Pedrazzi et al, 2015;Renard et al, 2016b). ...
Emerging evidence suggests that the largest phytochemical component of cannabis, cannabidiol (CBD), may possess pharmacotherapeutic properties in the treatment of neuropsychiatric disorders. CBD has been reported to functionally interact with both the mesolimbic dopamine (DA) and serotonergic (5-HT) receptor systems. However, the underlying mechanisms by which CBD may modulate emotional processing are not currently understood. Using a combination of in vivo electrophysiological recording and fear conditioning in rats, the present study aimed to characterize the behavioral, neuroanatomical and pharmacological effects of CBD within the mesolimbic pathway, and its possible functional interactions with 5-HT and DAergic transmission. Using targeted microinfusions of CBD into the shell region of the mesolimbic nucleus accumbens (NASh), we report that intra-NASh CBD potently blocks the formation of conditioned freezing behaviors. These effects were challenged with DAergic, cannabinoid CB1 receptor and serotonergic (5-HT1A) transmission blockade, but only 5-HT1A blockade restored associative conditioned freezing behaviors. In vivo intra-VTA electrophysiological recordings revealed that behaviorally effective doses of intra-NASh CBD elicited a predominant decrease in spontaneous DAergic neuronal frequency and bursting activity. These neuronal effects were reversed by simultaneous blockade of 5-HT1A receptor transmission. Finally, using a functional contralateral dis-connection procedure, we demonstrated that the ability of intra-NASh CBD to block the formation of conditioned freezing behaviors was dependent upon intra-VTA GABAergic transmission substrates. Our findings demonstrate a novel NAcVTA circuit responsible for the behavioral and neuronal effects of CBD within the mesolimbic system via functional interactions with serotonergic 5-HT1A receptor signalling.Neuropsychopharmacology accepted article preview online, 14 June 2016. doi:10.1038/npp.2016.93.
... Mijangos-Moreno et al. were the first researchers who identified a relationship between CBD and adenosine concentration. They found that injecting CBD into the hypothalamus of rats boosted extracellular levels of adenosine in the nucleus accumbens [55]. Adenosine reuptake and signaling are both stimulated by CBD. ...
... Mijangos-Moreno et al. were the first researchers who identified a relationship between CBD and adenosine concentration. They found that injecting CBD into the hypothalamus of rats boosted extracellular levels of adenosine in the nucleus accumbens [55]. Adenosine reuptake and signaling are both stimulated by CBD. ...
Cannabis sativa has long been used for neurological and psychological healing. Recently, cannabidiol (CBD) extracted from cannabis sativa has gained prominence in the medical field due to its non-psychotropic therapeutic effects on the central and peripheral nervous systems. CBD, also acting as a potent antioxidant, displays diverse clinical properties such as anticancer, antiinflammatory, antidepressant, antioxidant, antiemetic, anxiolytic, antiepileptic, and antipsychotic effects. In this review, we summarized the structural activity relationship of CBD with different receptors by both experimental and computational techniques and investigated the mechanism of interaction between related receptors and CBD. The discovery of structural activity relationship between CBD and target receptors would provide a direction to optimize the scaffold of CBD and its derivatives, which would give potential medical applications on CBD-based therapies in various illnesses.
Graphical Abstract
... Considering the widespread physiological effects of the ECS and the multiple target actions of CBD, it is important to consider other potential mechanisms beyond 5-HT 1A activation. Mijangos et al.'s research proved that intrahypothalamic injection of cannabidiol induced elevated extracellular adenosine levels in the nucleus accumbens [48]. Jurič et al. also reported that CBD modulates adenosine release from astrocytes affecting their extracellular accumulation [49]. ...
Cannabis sativa has been used for improving sleep for long history. Cannabidiol (CBD) has drown much attention as a non-addictive psychoactive component in Cannabis sativa extract. However, the effects of CBD on sleep architecture and it’s acting mechanism remains unclear. In the present study, we evaluated the sedative-hypnotic effect of cannabidiol (CBD), assessed the effects of CBD on sleep using a wireless physiological telemetry system. We further explored the therapeutic effects of CBD using 4-chloro-dl-phenylalanine (PCPA) induced insomnia model and changes in sleep latency, sleep duration and intestinal flora were evaluated. CBD shortened sleep latency and increases sleep duration in both normal and insomnia mice, and those effects were blocked by 5-HT1A receptor antagonist WAY100635. We determined that CBD increases 5-HT1A receptors expression and 5-HT content in the hypothalamus of PCPA-pretreated mice and affects tryptophan metabolism in the intestinal flora. These results showed that activation of 5-HT1A receptors is one of the potential mechanisms underlying the sedative-hypnotic effect of CBD. This study validated the effects of CBD on sleep and evaluated its potential therapeutic effects on insomnia.
... Cannabidiol (CBD) is a phytocannabinoid with documented anti-epilepsy effects and has been approved by the FDA for the treatment of Dravet Syndrome. CBD exerts its anti-epilepsy effects through various mechanisms, one of which involves the adenosine system [34,35,36]. Furthermore, CBD exhibits potent anti-in ammatory effects in various disease models, e ciently reducing the production of cytokines such as TNFα, IFN-γ, and IL-6, which are involved in neurotoxic reactive astrocytes formation in AD mice model. ...
Reactive astrocytes play a critical role in the pathology of various neurological disorders, often resulting in neuronal damage and death. Accumulating evidences demonstrate that reactive astrocyte is an important component of glia scar of epileptic human brain, but the molecular subtyping and functional characterization of reactive astrocytes in the initiation and progression of epilepsy is not fully understood. In this study, we report the existence of neurotoxic reactive astrocytes, a novel defined reactive astrocyte subtype, that are pro-epileptic in the epileptic brain. In a kainic acid-induced mouse model of epilepsy, these neurotoxic reactive astrocytes are induced by microglia-secreted cytokines IL-1α, TNFα, and C1q and formed in the mouse brain as early as seven days post kainic acid stimulation. These cells exhibit a distinct molecular signature marked by elevated expression of complement 3 and adenosine 2A receptor. Transcriptomics and metabolomics analyses using brain tissues from patients with temporal lobe epilepsy and epileptic mice reveal that neurotoxic reactive astrocytes contribute to neuronal loss through lipid-related mechanisms. Moreover, our study demonstrated that the anti-epileptic drug cannabidiol and an adenosine 2A receptor antagonist can suppress the formation of neurotoxic reactive astrocytes. These compounds also exhibit pronounced effects in inhibiting gliosis and neuronal loss in mouse models of epilepsy. Electrophysiological and behavioral studies provide compelling evidences that cannabidiol attenuates seizure symptoms and enhances memory capabilities in epileptic mice. Our findings suggest that neurotoxic reactive astrocytes are formed at an early stage in the epileptic mouse brain and can lead to neuronal death through releasing toxic lipids. Importantly, cannabidiol and adenosine 2A receptor antagonist emerge as promising therapeutic candidates for epilepsy treatment. Our study provides valuable insights into the mechanism of action of cannabidiol in epilepsy and opens avenues for targeted interventions against neurotoxic reactive astrocytes in neurological disorders.
... Its activation leads to an increase in intracellular calcium ion concentrations, consistent with heightened neuronal excitability, and its expression is also seemingly elevated in epileptic hippocampus. 115,116 Further mechanistic studies have shown that intrahypothalamic injection of cannabidiol increases extracellular levels of adenosine in the nucleus accumbens, 117 an effect that is believed to be mediated by inhibition of adenosine reuptake via the ENT1 transporter into presynaptic nerve terminals and adjacent glial cells. 110 Adenosine is a well-characterised endogenous anticonvulsant and the elevation of extracellular adenosine concentrations is a further plausible explanation for the antiseizure activity of cannabidiol. ...
Developmental and epileptic encephalopathies (DEEs) are rare neurodevelopmental disorders characterised by early-onset and often intractable seizures and developmental delay/regression, and include Dravet syndrome and Lennox–Gastaut syndrome (LGS). Rufinamide, fenfluramine, stiripentol, cannabidiol and ganaxolone are antiseizure medications (ASMs) with diverse mechanisms of action that have been approved for treating specific DEEs. Rufinamide is thought to suppress neuronal hyperexcitability by preventing the functional recycling of voltage-gated sodium channels from the inactivated to resting state. It is licensed for adjunctive treatment of seizures associated with LGS. Fenfluramine increases extracellular serotonin levels and may reduce seizures via activation of specific serotonin receptors and positive modulation of the sigma-1 receptor. Fenfluramine is licensed for adjunctive treatment of seizures associated with Dravet syndrome and LGS. Stiripentol is a positive allosteric modulator of type-A gamma-aminobutyric acid (GABAA) receptors. As a broad-spectrum inhibitor of cytochrome P450 enzymes, its antiseizure effects may additionally arise through pharmacokinetic interactions with co-administered ASMs. Stiripentol is licensed for treating seizures associated with Dravet syndrome in patients taking clobazam and/or valproate. The mechanism(s) of action of cannabidiol remains largely unclear although multiple targets have been proposed, including transient receptor potential vanilloid 1, G protein-coupled receptor 55 and equilibrative nucleoside transporter 1. Cannabidiol is licensed as adjunctive treatment in conjunction with clobazam for seizures associated with Dravet syndrome and LGS, and as adjunctive treatment of seizures associated with tuberous sclerosis complex. Like stiripentol, ganaxolone is a positive allosteric modulator at GABAA receptors. It has recently been licensed in the USA for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder. Greater understanding of the causes of DEEs has driven research into the potential use of other novel and repurposed agents. Putative ASMs currently in clinical development for use in DEEs include soticlestat, carisbamate, verapamil, radiprodil, clemizole and lorcaserin.
... Indeed, CBD boosts AEA levels in rat brains in and in human serum via an N-acyl phosphatidylethanolamine phospholipase D dependent mechanism [87,88]. Another target for the anti-inflammatory and sedating effects of CBD is the blockade of adenosine uptake acting through the equilibrative nucleoside transporter (ENT) [89,90]. The ATP-binding cassette super-family G member 2 (ABCG2) or P-glycoprotein), and the multidrug resistance proteins (multidrug resistance-associated protein 1 (ABCC1) and Mg2+-ATPase also have shown to be modulated by CBD [91,92] (Figure 3). ...
The medical use of cannabis has a very long history. Although many substances called cannabinoids are present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD) and cannabinol (CBN) are the three main cannabinoids that are most present and described. CBD itself is not responsible for the psychotropic effects of cannabis, since it does not produce the typical behavioral effects associated with the consumption of this drug. CBD has recently gained growing attention in modern society and seems to be increasingly explored in dentistry. Several subjective findings suggest some therapeutic effects of CBD that are strongly supported by research evidence. However, there is a plethora of data regarding CBD’s mechanism of action and therapeutic potential, which are in many cases contradictory. We will first provide an overview of the scientific evidence on the molecular mechanism of CBD’s action. Furthermore, we will map the recent developments regarding the possible oral benefits of CBD. In summary, we will highlight CBD’s promising biological features for its application in dentistry, despite exiting patents that suggest the current compositions for oral care as the main interest of the industry.
... Indeed, CBD boosts AEA levels in rat brains in and in human serum via an N-acyl phosphatidylethanolamine phospholipase D dependent mechanism [87,88]. Another target for the anti-inflammatory and sedating effects of CBD is the blockade of adenosine uptake acting through the equilibrative nucleoside transporter (ENT) [89,90]. ATP-binding cassette super-family G member 2 (ABCG2) or P-glycoprotein), multidrug resistance proteins (multidrug resistance-associated protein 1 (ABCC1) and Mg2+-ATPase also have been showed to be modulated by CBD [91,92] (Figure 3). ...
The medical use of Cannabis has a very long history. Although many principles are present in cannabis, called cannabinoids, Δ9tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD) and can-nabinol (CBN) are the three main cannabinoids most present and described. CBD itself is not re-sponsible for psychotropic effects of cannabis since does not produce the typical behavioral effects associated to the consumption of this drug. Cannabidiol (CBD) has recently gained growing at-tention in modern society and seems to be more and more explored in dentistry. Several subjective findings suggest some therapeutic effects of CBD, which are strongly supported by research evi-dence. However, there is a plethora of data regarding CBD’s mechanism of action and therapeutic potential, which are in many cases contradictory. We will first provide an overview of scientific evidence on the molecular mechanism of CBD’s action. Furthermore, we will map the recent de-velopments regarding possible oral benefits of CBD. In summary, we will highlight CBD’s prom-ising biological features for dentistry application, despite exiting patents suggest current the compositions for oral care as the main interest for industry.
... Experimental evidence supports an impact of CBD on adenosinemediated signaling processes . In particular, CBD can increase extracellular concentrations of adenosine based on inhibition of cellular reuptake of purine (Liou et al., 2008;Mijangos-Moreno et al., 2014;. Thus, it has been suggested that the inhibition of adenosine transport and associated enhancement of adenosine signaling may contribute to the antiseizure effect of CBD . ...
The anticonvulsant effect of cannabidiol (CBD), which has been confirmed by findings from animal models and human trials, has attracted the interest of veterinary practitioners and dog owners. Moreover, social media and public pressure has sparked a renewed awareness of cannabinoids, which have been used for epilepsy since ancient times. Unfortunately, at this moment veterinarians and veterinary neurologists have difficulty prescribing cannabinoids because of the paucity of sound scientific studies. Pharmacokinetic studies in dogs have demonstrated a low oral bioavailability of CBD and a high first-pass effect through the liver. Administering CBD in oil-based formulations and/or with food has been shown to enhance the bioavailability in dogs, rats and humans. Tolerability studies in healthy dogs and dogs with epilepsy have demonstrated that CBD was safe and well tolerated with only mild to moderate adverse effects. In this context, it should be noted that the quality of available CBD varies widely, underscoring the importance of pharmaceutical quality and its control. One clinical trial in dogs with drug-resistant idiopathic epilepsy failed to confirm a difference in response rates between the CBD group and the placebo group, while in another cross-over trial a ≥ 50% reduction in epileptic seizure frequency was found in six of 14 dogs in the treatment phase, a reduction that was not observed during the placebo phase. Based on the current state of knowledge it is not possible to provide clear-cut recommendations for the use of CBD in canine epilepsy. Randomized controlled canine trials with large sample sizes are needed to determine the range of therapeutic plasma concentrations, develop evidence-based dosing regimens, determine the efficacy of cannabidiol in drug-refractory epilepsy, and explore potential associations between treatment effects and different etiologies, epilepsy types, and drug combinations.
... Cannabinoids have been shown to promote wakefulness in a few studies. [45][46][47] On the other hand, cannabis products are associated with a significant side effect of daytime sedation. One study examined the effects of THC and CBD versus placebo in young adults on subjective measures of nighttime sleep as well as morning sleepiness assessed for 30 min after rising and 9 h after administration of THC and/or CBD. ...
The use of cannabis products to help with sleep and various other medical conditions by the public has increased significantly in recent years. Withdrawal from cannabinoids can lead to sleep disturbance. Here, we describe a patient who developed significant insomnia leading to worsening anxiety, mood, and suicidal ideation in the setting of medical cannabis withdrawal, prompting presentation to the Emergency Department and inpatient admission. There is a limited evidence base for the use of cannabis products for sleep. We provide a comprehensive review evaluating the literature on the use of cannabis products on sleep, including an overview of cannabis and related psychoactive compounds, the current state of the law as it pertains to the prescribing and use of these substances, and potential side effects and drug interactions. We specifically discuss the impact of cannabis products on normal sleep and circadian sleep-wake rhythms, insomnia, excessive daytime sleepiness, sleep apnea, parasomnias, and restless legs syndrome. We also describe the effects of cannabis withdrawal on sleep and how this increases relapse to cannabis use. Most of the studies are observational but the few published randomized controlled trials are reviewed. Our comprehensive review of the effects of cannabis products on normal sleep and sleep disorders, relevant to primary care providers and other clinicians evaluating and treating patients who use these types of products, shows that cannabis products have minimal to no effects on sleep disorders and may have deleterious effects in some individuals. Further research examining the differential impact of the various types of cannabinoids that are currently available on each of these sleep disorders is required.
... The endocannabinoid system has been investigated for its role in various types of pain including CIPN and offers several molecular targets that could be antinociceptive [96,97]. Cannabidiol (FDA-approved for rare pediatric seizure disorders) has multiple mechanisms of antinociceptive action within and beyond the endocannabinoid system, including reuptake inhibition of anandamide and adenosine, FAAH inhibition, allosteric modulator at CB 2 receptors and at muand delta-opioid receptors, antagonist at GPR55 (orphan cannabinoid) receptors, TRPV1 agonist, 5HT 1A agonist, and PPARα agonist [98][99][100][101][102]. Notably, CBD and a more target-selective structural analog, KLS-13019, were shown to reduce paclitaxel-induced mechanical allodynia, mediated partly through 5HT 1A (but not CB 1 or CB 2 ) receptors and the mitochondrial Na + Ca 2+ exchanger-1, in a mouse model of CIPN [103,104]. ...
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious and often persistent adverse consequence of certain chemotherapeutic agents. It is a major dose-limiting factor of many first-line chemotherapies, affecting 20–50% of patients at standard doses and nearly all patients at high doses. As cancer survivorship continues to increase with improvements in early diagnosis and treatment, more patients will experience CIPN despite completing cancer treatment, which interferes with recovery, leading to chronic pain and worsening quality of life. The National Cancer Institute has identified CIPN as a priority in translational research. To date, there are no FDA-approved drugs for preventing or treating CIPN, with emerging debate on mechanisms and promising new targets. This review highlights current literature and suggests novel approaches to CIPN based on proposed mechanisms of action that aim either to confer neuroprotection against chemotherapy-induced neurotoxicity or reverse the downstream effects of painful neuropathy. © 2021, The American Society for Experimental NeuroTherapeutics, Inc.
... In addition, the current report describes the disturbances in metabolic markers activity in adult rats treated during juvenile ages with chronic administration of CBD, but it remains to explore whether the reported effects are permanent. Besides, due to CBD engages non-endocannabinoid signaling systems, such as cholinergic, adenosinergic, monoaminergic, serotonergic, glycinergic networks (Bih et al., 2015;Mijangos-Moreno et al., 2014;Murillo-Rodríguez et al, 2011, thus it is not yet known which of these mechanisms might be presumably responsible for the reported effects. Furthermore, we did not test whether adult rats that received during the adolescence chronic injections of CBD displayed cardiac disturbances or developed obesity, anemia, diabetes or evaluated developmental mechanisms perturbed during the treatments leading to long-lasting neurobiological, and metabolic consequences. ...
The use of cannabidiol (CBD), the non-psychotropic compound derived from Cannabis sativa, for therapeutic purposes is growing exponentially by targeting the management of multiple medical disorders, including metabolism-related diseases. Nevertheless, substantial questions have emerged in concerning the potential metabolic disturbances in adulthood as consequence of the long-term uses of CBD during early years of life. Therefore, we studied whether chronic CBD injections (5, 10 or 30 mg/kg; i.p.) given to juvenile rats (from post-natal day [PND] 30) for 14 days might influence in adulthood the activity of metabolic markers, such as glucose, total cholesterol, triglycerides as well as activity of antioxidants (DPPH) from plasma, white adipose tissue (WAT), brown adipose tissue (BAT), liver, and hypothalamus. Our results showed that adult rats treated during juvenile ages with CBD (5, 10 or 30 mg/kg) for two weeks increased the contents of glucose whereas with no changes on total cholesterol in adulthood were observed. Additionally, a significant decrease in the levels of triglycerides were found in plasma, WAT, BAT, and liver in adult rats treated with chronic injections of CBD during the adolescence. However, unexpectedly, the contents of triglycerides in hypothalamus were found enhanced. Finally, the DPPH assay showed a significant enhancement in triglycerides analyzed from WAT and liver whereas opposite findings were observed in BAT and no significant changes were found in hypothalamus in adult rats that received during the adolescence chronic injections of CBD. In conclusion, repeated CBD administration to juvenile rats induced significant alterations in multiple metabolic markers analyzed in the adulthood. Our findings highlight the relevance of chronic CBD treatment in disturbed metabolic activity and remark the need for studying the underlying mechanisms involved.
... Interestingly, there is some evidence that CBD modulates various neural circuits and behavioral outcomes involved in drug addiction (Calpe-López et al., 2019). For example, CBD raises the threshold for the activation of the brain reward mechanisms mediated by the increase of mesocorticolimbic dopamine (DA) release after drug administration (Katsidoni et al., 2013;Mijangos-Moreno et al., 2014;Murillo-Rodríguez et al., 2011). Intra-accumbal infusion of CBD reverses the increase in the firing frequency of DA in the ventral tegmental area (VTA), psychomotor sensitization effects, and deficits in pre-pulse inhibition after an amphetamine challenge in rats (Pedrazzi et al., 2015;Renard et al., 2016). ...
Cocaine dependence is a highly prevalent disease in modern society and lacks an effective treatment. Cannabidiol (CBD), a major non-psychoactive constituent of Cannabis sativa, has been shown to be a promising tool in the management of some neuropsychiatric disorders, including cocaine abuse. However, its therapeutic effects on the behavioral outcomes related to cocaine addiction remain unclear. The present research evaluates the effects of CBD (30, 60 and 120 mg/kg; injected intraperitoneally) on the acquisition, expression, extinction and reinstatement of cocaine (10 mg/kg)-induced conditioned place preference (CPP; Study 1); cocaine (25 mg/kg)-induced locomotor stimulation (Study 2); and cocaine withdrawal symptoms (Study 3) in male C57BL/6 J mice. The results show that CBD does not possess motivational properties in itself and does not modify the acquisition, expression or extinction of cocaine-induced CPP. Interestingly, when administered during the extinction phase of the cocaine-induced CPP, CBD (30 and 60 mg/kg) prevented priming-induced reinstatement of CPP. Moreover, CBD abolished cocaine-induced hyperactivity without altering the spontaneous locomotion of the animals. Furthermore, CBD (120 mg/kg) reduced the memory deficits induced by cocaine withdrawal in the object recognition test, though it did not reverse depressive-like symptoms measured in the tail suspension test. Overall, our data suggest that CBD can prevent the development of cocaine addiction, and, when administered during cocaine abstinence, may be of help in avoiding relapse to drug-seeking and in ameliorating the memory disturbances provoked by chronic consumption of cocaine.
... Cannabidiol (CBD) acts via multiple eCB mechanisms including CB 1 negative allosteric modulation, 153,154 and inhibition of anandamide reuptake, 155 thereby increasing eCB signaling. CBD also has non-eCB pharmacological actions including inhibition of adenosine reuptake 156 and 5HT 1A partial agonism, 157 each of which can promote sleep. At higher doses, CBD is sedating. ...
Due to the ongoing opioid epidemic, innovative scientific perspectives and approaches are urgently needed to reduce the unprecedented personal and societal burdens of nonmedical and recreational opioid use. One promising opportunity is to focus on the relationship between sleep deficiency and opioid use. In this review, we examine empirical evidence: (1) at the interface of sleep deficiency and opioid use, including hypothesized bidirectional associations between sleep efficiency and opioid abstinence; (2) as to whether normalization of sleep deficiency might directly or indirectly improve opioid abstinence (and vice versa); and (3) regarding mechanisms that could link improvements in sleep to opioid abstinence. Based on available data, we identify candidate sleep-restorative therapeutic approaches that should be examined in rigorous clinical trials.
... Indeed, CBD administration increases AEA levels in rat brains in an N-acyl phosphatidylethanolamine phospholipase D dependent manner [45] and in human serum [46]. Moreover, low nanomolar concentrations of CBD (IC50 = 124 nM) inhibit equilibrative nucleoside transporter (ENT) and adenosine uptake, which underlies both the anti-inflammatory and possibly sleep promoting effects of CBD [47,48]. CBD activity for other transporter proteins, such as multidrug resistance proteins (multidrug resistance-associated protein 1 (ABCC1), ATP-binding cassette super-family G member 2 (ABCG2) or P-glycoprotein) or Mg2+-ATPase, has also been studied; however, IC50 values above 3000 nM suggest these to be physiologically irrelevant. ...
Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two components found in the highest concentrations. CBD itself does not produce typical behavioral cannabimimetic effects and was thought not to be responsible for psychotropic effects of cannabis. Numerous anecdotal findings testify to the therapeutic effects of CBD, which in some cases were further supported by research findings. However, data regarding CBD’s mechanism of action and therapeutic potential are abundant and omnifarious. Therefore, we review the basic research regarding molecular mechanism of CBD’s action with particular focus on its analgesic potential. Moreover, this article describes the detailed analgesic and anti-inflammatory effects of CBD in various models, including neuropathic pain, inflammatory pain, osteoarthritis and others. The dose and route of the administration-dependent effect of CBD, on the reduction in pain, hyperalgesia or allodynia, as well as the production of pro and anti-inflammatory cytokines, were described depending on the disease model. The clinical applications of CBD-containing drugs are also mentioned. The data presented herein unravel what is known about CBD’s pharmacodynamics and analgesic effects to provide the reader with current state-of-art knowledge regarding CBD’s action and future perspectives for research.
... The anticonvulsant mechanism of CBD in part may also depend on interaction with the purinergic system, although it does not show any level of affinity with adenosine receptors. However, studies demonstrate that CBD can promote an increase in the levels of extracellular adenosine in the nervous system, through inhibition of equilibrative necleoside trasporter-1 (ENT-1) (Fig. 5) (Mijangos-Moreno et al., 2014;Wright and Lee, 2019). ...
Epilepsy is a chronic neurological disease characterized by recurrent epileptic seizures. Studies have shown the complexity of epileptogenesis and ictogenesis, in which immunological processes and epigenetic and structural changes in neuronal tissues have been identified as triggering epilepsy. Cannabidiol (CBD) is a major active component of the Cannabis plant and the source of CBD-enriched products for the treatment of epilepsy and associated diseases. In this review, we provide an up-to-date discussion on cellular and molecular mechanisms triggered during epilepsy crises, and the phytochemical characteristics of CBD that make it an attractive candidate for controlling rare syndromes, with excellent therapeutic properties. We also discuss possible CBD anticonvulsant mechanisms and molecular targets in neurodegenerative disorders and epilepsy. Based on these arguments, we conclude that CBD presents a biotecnological potential in the anticonvulsant process, including decreasing dependence on health care in hospitals, and could make the patient's life more stable, with regard to neurological conditions.
... Moreover, previous reports have shown that histones are engaged in CBD-related effects [7,8]. Since we have previously reported that CBD promotes wakefulness [9][10][11][12], thus it was reasonable to hypothesize that this cannabinoid could exert influence on the histone activity in wake-related brain areas specially since histones have been linked to sleep modulation [13][14][15][16][17][18]. Therefore, we investigated the post-translational modification (PTM) on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels after systemic injections of CBD (20mg/Kg/i.p.) in the cerebral cortex, hypothalamus and pons of rats. ...
Background:
Cannabidiol (CBD), a non-psychotropic constituent of Cannabis sativa, has shown therapeutic promises by modulating several pathological conditions, including pain, epilepsy autism, among others. However, the molecular mechanism of action of CBD remains unknown and recent data suggest the engagement on CBD´s effects of nuclear elements, such as histone activity.
Aim:
This study assessed the changes on the post-translational modification (PTM) on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions of rats after the administration of CBD (20mg/Kg/i.p.).
Objective:
To evaluate the effects on the PTM of histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels in the cerebral cortex, hypothalamus and pons of CBD-treated rats.
Method:
Ten adult rats were randomly assigned into 2 groups: Control or CBD (20mg/Kg/i.p). Animals were sacrificed after treatments and brains were collected for dissections of the cerebral cortex, hypothalamus and pons. Samples were analyzed for PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels by Western blot procedure.
Results:
CBD increased the PTM levels on the histones H3K4Me3, H3K9ac, and H3K27Me3 in the cerebral cortex whereas no significant differences were found in H3K9Me2 and H3K36Me2. In addition, in the hypothalamus, CBD decreased the contents of H3K9ac while no significant effects were observed in H3K4Me3, H3K9Me2, H3K27Me3, and H3K36Me2. Lastly, in the pons, CBD-treated rats showed a significant decline on the PTM levels of H3K4Me3 whereas no statistical differences were found in H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2.
Conclusion:
The study showed that CBD induced differential effects in levels of PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions.
... Moreover, CBD seems to modulate diverse neurobiological functions, including the sleep-wake cycle. In this regard, it has been demonstrated that CBD enhances alertness as well as wake-related neurochemicals [35,[51][52][53][54]. Thus, we hypothesized that CBD might ameliorate the excessive sleepiness in narcoleptic-like animals. ...
Background
Excessive daytime sleepiness and cataplexy are among the symptoms of narcolepsy, a sleep disorder caused by the loss of hypocretin/orexin (HCRT/OX) neurons placed into the Hypothalamus (LH). Several treatments for managing narcolepsy include diverse drugs to induce alertness, such as antidepressants, amphetamine, or modafinil, etc. Recent evidence has shown that cannabidiol (CBD), a non-psychotropic derived from Cannabis sativa, shows positive therapeutic effects in neurodegenerative disorders, including Parkinson´s disease. Furthermore, CBD provokes alertness and enhances wake-related neurochemicals in laboratory animals. Thus, it is plausible to hypothesize that excessive somnolence observed in narcolepsy might be blocked by CBD.
Objective
Here, we determined whether the systemic injection of CBD (5mg/kg, i.p.) would block the excessive sleepiness in a narcoleptic model.
Methods
To test this idea, the neurotoxin hypocretin-2-saporin (HCRT2/SAP) was bilaterally injected into the LH of rats to eliminate HCRT leading to the establishment of narcoleptic-like behavior. Since excessive somnolence in HCRT2/SAP lesioned rats has been observed during the lights-off period, CBD was administered at the beginning of the dark phase.
Results
Hourly analysis of sleep data showed that CBD blocked the sleepiness during the lights-off period across 7h post-injection in lesioned rats.
Conclusion
Taking together, these preliminary findings suggest that CBD might prevent sleepiness in narcolepsy.
... To increase awareness in regards to putative effects derived from long-term uses of CBD, various reports have demonstrated that this phytocannabinoid engages multiple neurobiological systems [148], including the increase of the extracellular contents of acetylcholine, adenosine, dopamine, and serotonin [159][160][161]. Since it has not been described which of these neurobiological pathways could be responsible for the presumably therapeutic properties of CBD, then Fig. (2). ...
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.
... Secondly, CBD could attenuate the psychostimulant drug-induced dysregulation of the dopaminergic mesolimbic system. It has been demonstrated that the intrahypothalamic administration of CBD increased levels of DA and adenosine in the NAcc [65,66] while systemic administration of CBD increased c-fos expression in this structure but not in the dorsal striatum [67]. A recent study also demonstrated that the administration of CBD significantly reduced relative gene expression of tyrosine hydroxylase in the ventral tegmental area (VTA) [68]. ...
Currently, there are no approved pharmacotherapies for addiction to cocaine and other psychostimulant drugs. Several studies have proposed that cannabidiol (CBD) could be a promising treatment for substance use disorders. In the present work, the authors describe the scarce preclinical and human research about the actions of CBD on the effects of stimulant drugs, mainly cocaine and methamphetamine (METH). Additionally, the possible mechanisms underlying the therapeutic potential of CBD on stimulant use disorders are reviewed. CBD has reversed toxicity and seizures induced by cocaine, behavioural sensitization induced by amphetamines, motivation to self-administer cocaine and METH, context- and stress-induced reinstatement of cocaine and priming-induced reinstatement of METH seeking behaviours. CBD also potentiated the extinction of cocaine- and amphetamine-induced conditioned place preference (CPP), impaired the reconsolidation of cocaine CPP and prevented priming-induced reinstatement of METH CPP. Observational studies suggest that CBD may reduce problems related with crack-cocaine addiction, such as withdrawal symptoms, craving, impulsivity and paranoia (Fischer et al., 2015). The potential mechanisms involved in the protective effects of CBD on addiction to psychostimulant drugs include the prevention of drug-induced neuroadaptations (neurotransmitter and intracellular signalling pathways changes), the erasure of aberrant drug-memories, the reversion of cognitive deficits induced by psychostimulant drugs and the alleviation of mental disorders comorbid with psychostimulant abuse. Further, preclinical studies and future clinical trials are necessary to fully evaluate the potential of CBD as an intervention for cocaine and methamphetamine addictive disorders.
... Adenosine uptake inhibitor and indirect A2A agonist ? (Carrier et al., 2006;Cheffer et al., 2018;Liou et al., 2008;Mecha et al., 2013;Mijangos-Moreno et al., 2014;Nazario et al., 2015;Oláh et al., 2014). ...
Significant limitations with the currently available antidepressant treatment strategies have inspired research on finding new and more efficient drugs to treat depression. Cannabidiol (CBD)is a non-psychotomimetic component of Cannabis sativa, and emerges in this regard as a promising compound. In 2010, we were the first laboratory to demonstrate that CBD is effective in animal models of predictive of antidepressant effect, a finding now confirmed by several other groups. Recent evidence suggests that CBD promotes both a rapid and a sustained antidepressant effect in animal models. CBD has a complex pharmacology, with the ability to interact with multiple neurotransmitter systems involved in depression, including the serotonergic, glutamatergic, and endocannabinoid systems. Moreover, CBD induces cellular and molecular changes in brain regions related to depression neurobiology, such as increased Brain Derived Neurotrophic Factor (BDNF)levels and synaptogenesis in the medial prefrontal cortex, as well as it increases neurogenesis in the hippocampus. This review presents a comprehensive critical overview of the current literature related to the antidepressant effects of CBD, with focus at the possible mechanisms. Finally, challenges and perspectives for future research are discussed.
... The eCB cannabidiol (CBD) has diverse neuropharmacological actions but salient among these includes enhancing AEA levels with weak antagonist actions at CB 1 and CB 2 receptors (Campos et al., 2012;Izzo et al., 2009;Kathman et al., 2006;McPartland et al., 2015;Mijangos-Moreno et al., 2014;Pertwee, 2008;Petitet et al., 1998;Russo et al., 2005;Thomas et al., 2007). Transdermal CBD administration was recently found to attenuate acute and repeated YOH-reinstatement of cocaine and alcohol seeking and produced anxiolytic and anti-impulsive effects without disrupting other reward behavior or locomotion, and this profile of effects endured long after CBD was biologically detectable (Gonzalez-Cuevas et al., 2018). ...
Stress-related substance use is a major challenge for treating substance use disorders. This selective review focuses on emerging pharmacotherapies with potential for reducing stress-potentiated seeking and consumption of nicotine, alcohol, marijuana, cocaine, and opioids (i.e., key phenotypes for the most commonly abused substances). I evaluate neuropharmacological mechanisms in experimental models of drug-maintenance and relapse, which translate more readily to individuals presenting for treatment (who have initiated and progressed). An affective/motivational systems model (three dimensions: valence, arousal, control) is mapped onto a systems biology of addiction approach for addressing this problem. Based on quality of evidence to date, promising first-tier neurochemical receptor targets include: noradrenergic (α1 and β antagonist, α2 agonist), kappa-opioid antagonist, nociceptin antagonist, orexin-1 antagonist, and endocannabinoid modulation (e.g., cannabidiol, FAAH inhibition); second-tier candidates may include corticotropin releasing factor-1 antagonists, serotonergic agents (e.g., 5-HT reuptake inhibitors, 5-HT3 antagonists), glutamatergic agents (e.g., mGluR2/3 agonist/positive allosteric modulator, mGluR5 antagonist/negative allosteric modulator), GABA-promoters (e.g., pregabalin, tiagabine), vasopressin 1b antagonist, NK-1 antagonist, and PPAR-γ agonist (e.g., pioglitazone). To address affective/motivational mechanisms of stress-related substance use, it may be advisable to combine agents with actions at complementary targets for greater efficacy but systematic studies are lacking except for interactions with the noradrenergic system. I note clinically-relevant factors that could mediate/moderate the efficacy of anti-stress therapeutics and identify research gaps that should be pursued. Finally, progress in developing anti-stress medications will depend on use of reliable CNS biomarkers to validate exposure-response relationships.
... All rights reserved. (Mijangos-Moreno et al. 2014)B 39 4 ( Moss et al. 1995) 40 -190 ( Nelson et al. 2009)B 42 6.3 (Andine et al. 1990) 47 49.9 9.1 (?) (Dux et al. 1990 et al. 1989) 90 (Chen et al. 1992) 100 10 ( Hillered et al. 1989) 100 0 ( Kaku et al. 1994 190 (Yan et al. 1995) 190 40 (Ballarin et al. 1987 200 30 ( Gidday et al. 1996) 200 28 ( Grabb et al. 1998)A 200 (Headrick et al. 1994 200 ...
Microdialysis is a method to study the extracellular space in vivo, based on the principle of diffusion. It can be used to measure various small molecules including the neuroregulator adenosine. Baseline levels of the compounds measured with microdialysis vary over studies.
We systematically reviewed the literature to investigate the full range of reported baseline concentrations of adenosine and AMP in microdialysates. We performed a meta‐regression analysis to study the influence of flow rate, probe membrane surface area, species, brain area, and anaesthesia versus freely behaving, on the adenosine concentration.
Baseline adenosine concentrations in microdialysates ranged from 0.8 to 2100 nM. There was limited evidence on baseline AMP concentrations in microdialysates. Across studies, we found effects of flow rate and anaesthesia versus freely behaving on dialysate adenosine concentrations (p ≤ 0.001), but not of probe membrane surface, species, or brain area (P≥0.14). With increasing flow rate, adenosine concentrations decreased. With anaesthesia, adenosine concentrations increased. The effect of other predictor variables on baseline adenosine concentrations, e.g. post‐surgical recovery time, could not be analysed due to a lack of reported data.
This study shows that meta‐regression can be used as an alternative to new animal experiments to answer research questions in the field of neurochemistry. However, current levels of reporting of primary studies are insufficient to reach the full potential of this approach; 63 out of 133 studies could not be included in the analysis due to insufficient reporting, and several potentially relevant factors had to be excluded from the analyses. The level of reporting of experimental detail needs to improve.
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... Recently, Hsiao et al. (2012) reported that CBD blocked anxiety-induced REMS suppression. Lastly, the wake-promoting effects of CBD might engage neurochemicals related to control of waking such as adenosine (Mijangos-Moreno et al. 2014). Taken together, these data suggest that CBD promotes alertness. ...
Marijuana is a colloquial name given to Cannabis sativa, which has been used for diverse purposes, including as a therapeutical element for multiple health issues. The neurobiological effects of C. sativa involve a complex biological machinery including receptors, named CB1 and CB2 cannabinoid receptors. These receptors recognize endogenous cannabinoid-like compounds, such as anandamide and 2-arachinonolglycerol which seems to display sleep-inducing properties. Along decades, the study of the putative role of exogenous and endogenous cannabinoids in sleep modulation has brought critical data. Since endocannabinoids have been described in sleep-related brain areas, intriguing issues regarding whether hypothalamic substrates, such as MHC, may be interacting with the endocannabinoids have been raised.
... Japan). All procedure of detection of monoamines or AD was developed according to our previous reports (Murillo-Rodríguez et al., 2011;Mijangos-Moreno et al., 2014. ...
The peroxisome proliferator-activated receptor alpha (PPARα) is a member of the nuclear receptor superfamily that has been suggested as a modulator of several physiological functions. The PPARα recognizes as an endogenous ligand the anorexic lipid mediator oleoylethanolamide (OEA) which displays wake-inducing properties. Despite that recent evidence indicates that activation of PPARα by synthetic agonists such as Wy14643 enhances waking as well as the extracellular contents of wake-related neurotransmitters, the role of PPARα in sleep recovery after prolonged waking has not been fully described. Thus, the aim of this study was to characterize if PPARα regulates sleep rebound after total sleep deprivation (TSD). We report that after 6h of TSD activation of PPARα by pharmacological systemic administration of OEA (10, 20 or 30mg/Kg, i.p.) promoted alertness by blocking the sleep rebound after TSD. Besides, wake-linked compounds such as dopamine, norepinephrine, serotonin, or adenosine collected from nucleus accumbens were enhanced after TSD in OEA-treated animals. These sleep and neurochemical results were mimicked after injection of PPARα agonist Wy14643 (10, 20, 30mg/Kg, i.p.). However, similar findings from the sham of vehicle groups were observed if PPARα antagonist MK-886 was administered to rats (10, 20, 30mg/Kg, i.p.). Our results strengthened the hypothesis that PPARα might modulate sleep and neurochemical homeostasis after sleep deprivation.
... Japan). All procedure of detection of monoamines or AD was developed according to our previous reports (Murillo-Rodríguez et al., 2011;Mijangos-Moreno et al., 2014. ...
... Enhancement of adenosine signaling, by inhibition of its uptake, has been proposed to mediate part of the anti-inflammatory, immunosuppressive, neuroprotective and behavioral effects of CBD [101]. Consistent with this proposal, CBD increased extra-cellular levels of adenosine [102]. Moreover, A2A receptor antagonists prevented CBD effects in a model of multiple sclerosis [30], the neuroprotection observed in brain slices of newborn mice after hypoxia and glucose deprivation [51], and rat microglial activation by LPS [103]. ...
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.
The sleep-wake cycle is a complex composition of specific physiological and behavioral characteristics. In addition, neuroanatomical, neurochemical and molecular systems exerts influences in the modulation of the sleep-wake cycle. Moreover, homeostatic and circadian mechanisms interact to control the waking or sleeping states. As many other behaviors, sleep also develops pathological features that include several signs and symptoms corresponding to medical conditions known as sleep disorders.In addition to the neurobiological mechanisms modulating sleep, external elements also influence the sleep-wake cycle, including the use of Cannabis sativa (C. sativa). In this regard, and over the last decades, the interest of studying the pharmacology of Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive constituent of C. sativa, has been addressed. Moreover, in recent years, the focus of scientific interest has moved on to studying the second plant constituent with non-psychotropic pharmacological properties: Cannabidiol (CBD).The pharmacological and pharmaceutical interest of CBD has been focus of attention due to the accumulating body of evidence regarding the positive outcomes of using CBD for the treatment of several health issues, such as psychiatric and neurodegenerative disorders, epilepsy, etc. Since the most prominent sleep disruptions include excessive daytime sleepiness (EDS), current treatments include the use of drugs such as stimulants of antidepressants. Notwithstanding, side effects are commonly reported among the patients under prescription of these compounds. Thus, the search of novelty therapeutical approaches aimed to treat ESD may consider the use of cannabinoid-derived compounds, such as CBD. In this chapter, we will show experimental evidence regarding the potential role of CBD as a wake-inducing compound aimed to manage EDS.
The therapeutic potential of cannabidiol (CBD) in seizure disorders has been known for many years, but it is only in the last decade that major progress has been made in characterizing its preclinical and clinical properties as an antiseizure medication. The mechanisms responsible for protection against seizures are not fully understood, but they are likely to be multifactorial and to include, among others, antagonism of G protein-coupled receptor, desensitization of transient receptor potential vanilloid type 1 channels, potentiation of adenosine-mediated signaling, and enhancement of GABAergic transmission. CBD has a low and highly variable oral bioavailability, and can be a victim and perpetrator of many drug-drug interactions. A pharmaceutical-grade formulation of purified CBD derived from Cannabis sativa has been evaluated in several randomized placebo-controlled adjunctive-therapy trials, which resulted in its regulatory approval for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Interpretation of results of these trials, however, has been complicated by the occurrence of an interaction with clobazam, which leads to a prominent increase in the plasma concentration of the active metabolite N-desmethylclobazam in CBD-treated patients. Despite impressive advances, significant gaps in knowledge still remain. Areas that require further investigation include the mechanisms underlying the antiseizure activity of CBD in different syndromes, its pharmacokinetic profile in infants and children, potential relationships between plasma drug concentration and clinical response, interactions with other co-administered medications, potential efficacy in other epilepsy syndromes, and magnitude of antiseizure effects independent from interactions with clobazam.
This article is part of the special issue on ‘Cannabinoids’.
Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States and as EPIDYOLEX from the EU agency) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials. While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy. Here we present the pharmacological data supporting the role of three such targets, namely Transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1).
Appendix S1. Study characteristics of papers reporting baseline adenosine concentrations.
Appendix S2. Study characteristics of papers and abstracts not reporting absolute baseline adenosine concentrations or only reporting them in low‐resolution figures.
Appendix S3. Adenosine monophosphate concentrations and corresponding study characteristics.
Dravet syndrome (DS) is a medically refractory epilepsy that onsets in the first year of life with prolonged seizures, often triggered by fever. Over time, patients develop other seizure types (myoclonic, atypical absences, drops), intellectual disability, crouch gait and other co-morbidities (sleep problems, autonomic dysfunction). Complete seizure control is generally not achievable with current therapies, and the goals of treatment are to balance reduction of seizure burden with adverse effects of therapies. Treatment of co-morbidities must also be addressed, as they have a significant impact on the quality of life of patients with DS. Seizures are typically worsened with sodium-channel agents. Accepted first-line agents include clobazam and valproic acid, although these rarely provide adequate seizure control. Benefit has also been noted with topiramate, levetiracetam, the ketogenic diet and vagal nerve stimulation. Several agents presently in development, specifically fenfluramine and cannabidiol, have shown efficacy in clinical trials. Status epilepticus is a recurring problem for patients with DS, particularly in their early childhood years. All patients should be prescribed a home rescue therapy (usually a benzodiazepine) but should also have a written seizure action plan that outlines when rescue should be given and further steps to take in the local hospital if the seizure persists despite home rescue therapy.
Growing clinical and pre-clinical evidence points to a critical role for cannabidiol (CBD), the largest phytochemical component of cannabis, as a potential pharmacotherapy for various neuropsychiatric disorders. In contrast to delta-9-tetrahydrocannabinol (THC), which is associated with acute and neurodevelopmental pro-psychotic side-effects, CBD possesses no known psychoactive or dependence-producing properties. However, evidence has demonstrated that CBD strongly modulates the mesolimbic dopamine (DA) system and may possess promising anti-psychotic properties. Despite the psychotropic differences between CBD and THC, little is known regarding their molecular and neuronal effects on the mesolimbic DA system, nor how these differential effects may relate to their potential pro vs. anti-psychotic properties. This review summarizes clinical and pre-clinical evidence demonstrating CBD’s modulatory effects on DA activity states within the mesolimbic pathway, functional interactions with the serotonin 5-HT1A receptor system, and their downstream molecular signaling effects. Together with clinical evidence showing that CBD may normalize affective and cognitive deficits associated with schizophrenia, CBD may represent a promising treatment for schizophrenia, acting through novel molecular and neuronal mesolimbic substrates.
BACKGROUND
Panic disorder (PD) is a disabling psychiatry condition that affects approximately 5% of the worldwide population. Currently, long-term selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for PD; however, the common side-effect profiles and drug interactions may provoke patients to abandon the treatment, leading to PD symptoms relapse. Cannabidiol (CBD) is the major non-psychotomimetic constituent of the Cannabis sativa plant with anti-anxiety properties that has been suggested as an alternative for treating anxiety disorders. The aim of the present review was to discuss the effects and mechanisms involved in the putative anti-panic effects of CBD.
METHODS
electronic database was used as source of the studies selected selected based on the studies found by crossing the following keywords: cannabidiol and panic disorder; canabidiol and anxiety, cannabidiol and 5-HT1A receptor).
RESULTS
In the present review, we included both experimental laboratory animal and human studies that have investigated the putative anti-panic properties of CBD. Taken together, the studies assessed clearly suggest an anxiolytic-like effect of CBD in both animal models and healthy volunteers.
CONCLUSION
CBD seems to be a promising drug for the treatment of PD. However, novel clinical trials involving patients with the PD diagnosis are clearly needed to clarify the specific mechanism of action of CBD and the safe and ideal therapeutic doses of this compound.
Sleep is not the mere absence of wakefulness, but an active state which is finely regulated. The homeostatic facet of sleep-wake regulation is keeping track of changes in 'sleep propensity' (or 'sleep need'), which increases during wakefulness and decreases during sleep. Increased sleep propensity following extended prior wakefulness (sleep deprivation) is counteracted by prolonged sleep duration, but also by enhanced non-rapid-eye-movement (nonREM) sleep intensity as measured by electroencephalographic (EEG) slow-wave activity (SWA, power within approximately 1-4 Hz). This highly reliable regulatory feature of nonREM sleep may be the most important aspect of sleep in relation to its function. The neurochemical mechanisms underlying nonREM sleep homeostasis are poorly understood. Here we provide compelling and convergent evidence that adenosinergic neurotransmission plays a role in nonREM sleep homeostasis in humans. Specifically, a functional polymorphism in the adenosine metabolizing enzyme, adenosine deaminase, contributes to the high inter-individual variability in deep slow-wave sleep duration and intensity. Moreover, the adenosine receptor antagonist, caffeine, potently attenuates the EEG markers of nonREM sleep homeostasis during sleep, as well as during wakefulness. Finally, adenosinergic mechanisms modulate individual vulnerability to the detrimental effects of sleep deprivation on neurobehavioral performance, and EEG indices of disturbed sleep after caffeine consumption. While these convergent findings strongly support an important contribution of adenosine and adenosine receptors to nonREM sleep homeostasis, further research is needed to elucidate the underlying mechanisms that mediate the actions of adenosine on sleep and the sleep EEG.
Unlabelled:
Cannabidiol (CBD) is one of the main components of Cannabis sativa and has a wide spectrum of action, including effects in the sleep-wake cycle.
Objective:
The objective of this paper is to assess the effects on sleep of acute systemic administration of CBD.
Method:
Adult male Wistar rats were randomly distributed into four groups that received intraperitoneal injections of CBD 2.5 mg/kg, CBD 10 mg/kg, CBD 40 mg/kg or vehicle (n=seven animals/group). Sleep recordings were made during light and dark periods for four days: two days of baseline recording, one day of drug administration (test), and one day after drug (post-test).
Results:
During the light period of the test day, the total percentage of sleep significantly increased in the groups treated with 10 and 40 mg/kg of CBD compared to placebo. REM sleep latency increased in the group injected with CBD 40 mg/kg and was significantly decreased with the dose of 10 mg/kg on the post-test day. There was an increase in the time of SWS in the group treated with CBD 40 mg/kg, although this result did not reach statistical significance.
Conclusion:
The systemic acute administration of CBD appears to increase total sleep time, in addition to increasing sleep latency in the light period of the day of administration.
Adenosine plays an important role in neuromodulation and neuroprotection. Recent identification of transient changes in adenosine concentration suggests adenosine may have a rapid modulatory role; however, the extent of these changes throughout the brain is not well understood. In this report, transient changes in adenosine evoked by one second, 60 Hz electrical stimulation trains were compared in the caudate-putamen, nucleus accumbens, hippocampus, and cortex. The concentration of evoked adenosine varies between brain regions, but there is less variation in the duration of signaling. The highest concentration of adenosine was evoked in the dorsal caudate-putamen (0.34 ± 0.08 μM), while the lowest concentration was in the secondary motor cortex (0.06 ± 0.02 μM). In all brain regions, adenosine release was activity-dependent. In the nucleus accumbens, hippocampus, and prefrontal cortex, this release was partly due to extracellular ATP breakdown. However, in the caudate-putamen, release was not due to ATP metabolism but was ionotropic glutamate receptor-dependent. The results demonstrate that transient, activity-dependent adenosine can be evoked in many brain regions but that the mechanism of formation and release varies by region.
We have previously shown that modafinil promotes wakefulness via dopamine receptor D(1) and D(2) receptors; however, the locus where dopamine acts has not been identified. We proposed that the nucleus accumbens (NAc) that receives the ventral tegmental area dopamine inputs play an important role not only in reward and addiction but also in sleep-wake cycle and in mediating modafinil-induced arousal.
In the present study, we further explored the role of NAc in sleep-wake cycle and sleep homeostasis by ablating the NAc core and shell, respectively, and examined arousal response following modafinil administration. We found that discrete NAc core and shell lesions produced 26.5% and 17.4% increase in total wakefulness per day, respectively, with sleep fragmentation and a reduced sleep rebound after a 6-hr sleep deprivation compared to control. Finally, NAc core but not shell lesions eliminated arousal effects of modafinil.
These results indicate that the NAc regulates sleep-wake behavior and mediates arousal effects of the midbrain dopamine system and stimulant modafinil.
The development of a simple and rapid high-performance liquid chromatography (HPLC) method for the determination of the new antiepileptic drug rufinamide (RFN) in human plasma and saliva is reported. Samples (250 μl) are alkalinized with ammonium hydroxide (pH 9.25) and extracted with dichloromethane using metoclopramide as internal standard. Separation is achieved with a Spherisorb silica column (250 × 4.6 mm i.d., 5 μm) at 30 °C using as mobile phase a solution of methanol/dichloromethane/n-hexane 10/25/65 (vol/vol/vol) mixed with 6 ml ammonium hydroxide. The instrument used was a Shimadzu LC-10Av chromatograph and flow rate was 1.5 ml min-1, with a LaChrom L-7400 UV detector set at 230 nm. Calibration curves are linear [r
2 = 0.998 ± 0.002 for plasma (n = 10) and r
2 = 0.999 ± 0.001 for saliva (n = 9)] over the range of 0.25–20.0 μg ml-1, with a limit of quantification at 0.25 μg ml-1. Precision and accuracy are within current acceptability standards. The assay is suitable for pharmacokinetic studies in humans and for therapeutic drug monitoring.
This paper presents an overview of the current knowledge about the role of adenosine in the sleep-wake regulation with a focus on adenosine in the central nervous system, regulation of adenosine levels, adenosine receptors, and manipulations of the adenosine system by the use of pharmacological and molecular biological tools. The endogenous somnogen prostaglandin (PG) D(2) increases the extracellular level of adenosine under the subarachnoid space of the basal forebrain and promotes physiological sleep. Adenosine is neither stored nor released as a classical neurotransmitter and is thought to be formed inside cells or on their surface, mostly by breakdown of adenine nucleotides. The extracellular concentration of adenosine increases in the cortex and basal forebrain during prolonged wakefulness and decreases during the sleep recovery period. Therefore, adenosine is proposed to act as a homeostatic regulator of sleep and to be a link between the humoral and neural mechanisms of sleep-wake regulation. Both the adenosine A(1) receptor (A(1)R) and A(2A)R are involved in sleep induction. The A(2A)R plays a predominant role in the somnogenic effects of PGD(2). By use of gene-manipulated mice, the arousal effect of caffeine was shown to be dependent on the A(2A)R. On the other hand, inhibition of wake-promoting neurons via the A(1)R also mediates the sleep-inducing effects of adenosine, whereas activation of A(1)R in the lateral preoptic area induces wakefulness, suggesting that A(1)R regulates the sleep-wake cycle in a site-dependent manner. The potential therapeutic applications of agonists and antagonists of these receptors in sleep disorders are briefly discussed.
The nucleus accumbens shell (AcbSh) is required to inhibit drug seeking after extinction training. Conversely, the lateral hypothalamus (LH), which receives projections from AcbSh, mediates reinstatement of previously extinguished drug seeking. We hypothesized that reversible inactivation of AcbSh using GABA agonists (baclofen/muscimol) would reinstate extinguished alcohol seeking and increase neuronal activation in LH. Rats underwent self-administration training for 4% (v/v) alcoholic beer followed by extinction. AcbSh inactivation reinstated extinguished alcohol seeking when infusions were made after, but not before, extinction training. We then used immunohistochemical detection of c-Fos as a marker of neuronal activity, combined with immunohistochemical detection of the orexin and cocaine- and amphetamine-related transcript (CART) peptides, to study the profile and phenotype of neural activation during reinstatement produced by AcbSh inactivation. AcbSh inactivation increased c-Fos expression in hypothalamus, as well as in paraventricular thalamus and amygdala. Within hypothalamus, there was an increase in the number of orexin and CART cells expressing c-Fos. Finally, we hypothesized that concurrent inactivation of LH would prevent reinstatement produced by inactivation of AcbSh alone. Our results confirmed this. Together, these findings suggest that AcbSh mediates extinction of reward seeking by inhibiting hypothalamic neuropeptide neurons. Reversible inactivation of the AcbSh removes this influence, thereby releasing hypothalamus from AcbSh inhibition and enabling reinstatement of reward seeking. These ventral striatal-hypothalamic circuits for extinction overlap with those that mediate satiety, and we suggest that extinction training inhibits drug seeking because it co-opts neural circuits originally selected to produce satiety.
Cannabidiol (CBD) is a constituent of Cannabis sativa that induces nonpsychotropic effects, and some of its biological actions in sleep have been described by the authors' group. Here, the authors report that when administered 10 or 20 microg/1 microl during the lights-on period directly into either lateral hypothalamus (LH) or dorsal raphe nuclei (DRN), which are wake-inducing brain areas, CBD enhanced wakefulness and decreased slow wave sleep and REM sleep. Furthermore, CBD increased alpha and theta power spectra but diminished delta power spectra. Additionally, CBD increased c-Fos expression in LH or DRN. These findings suggest that this cannabinoid is a wake-inducing compound that presumably activates neurons in LH and DRN.
A sample of hashish was extracted consecutively with petroleum ether, benzene, and methanol. When tested intravenously in
monkeys only the petroleum-ether fraction was active. This material was further fractionated. The only active compound isolated
was Δ1-tetrahydrocannabinol. Cannabinol, cannabidiol, cannabichromene, cannabigerol, and cannabicyclol when administered together
with Δ1-tetrahydrocannabinol do not cause a change in the activity of the latter, under the experimental conditions used. These results
provide evidence that, except for Δ1-tetrahydrocannabinol, no other major, psychotomimetically active compounds are present in hashish.
The plant-derived cannabinoids delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) both have immunosuppressive effects; although some effects of THC are mediated by the CB2 receptor, CB2 binds CBD weakly. In examining the effects of THC and CBD on microglial proliferation, we found that these compounds potently inhibit [3H]thymidine incorporation into a murine microglial cell line with no effect on cell cycle. Treatment with THC and CBD decreased [3H]thymidine uptake into microglia, with IC50 values that match inhibition of [3H]thymidine incorporation into DNA. CBD and, less potently, THC decreased uptake of [3H]adenosine to a similar extent as [3H]thymidine in both murine microglia and RAW264.7 macrophages. Binding studies confirm that CBD binds to the equilibrative nucleoside transporter 1 with a Ki < 250 nM. Because adenosine agonists have antiinflammatory effects, and because uptake of adenosine is a primary mechanism of terminating adenosine signaling, we tested the hypothesis that CBD is immunosuppressive because it enhances endogenous adenosine signaling. In vivo treatment with a low dose of CBD decreases TNFalpha production in lipopolysaccharide-treated mice; this effect is reversed with an A2A adenosine receptor antagonist and abolished in A2A receptor knockout mice. These studies demonstrate that CBD has the ability to enhance adenosine signaling through inhibition of uptake and provide a non-cannabinoid receptor mechanism by which CBD can decrease inflammation.
It is currently hypothesized that the drive to sleep is determined by the activity of the basal forebrain (BF) cholinergic neurons, which release adenosine (AD), perhaps because of increased metabolic activity associated with the neuronal discharge during waking, and the accumulating AD begins to inhibit these neurons so that sleep-active neurons can become active. This hypothesis grew from the observation that AD induces sleep and AD levels increase with wake in the basal forebrain, but surprisingly it still remains untested. Here we directly test whether the basal forebrain cholinergic neurons are central to the AD regulation of sleep drive by administering 192-IgG-saporin to lesion the BF cholinergic neurons and then measuring AD levels in the BF. In rats with 95% lesion of the BF cholinergic neurons, AD levels in the BF did not increase with 6 h of prolonged waking. However, the lesioned rats had intact sleep drive after 6 and 12 h of prolonged waking, indicating that the AD accumulation in the BF is not necessary for sleep drive. Next we determined that, in the absence of the BF cholinergic neurons, the selective adenosine A1 receptor agonist N6-cyclohexyladenosine, administered to the BF, continued to be effective in inducing sleep, indicating that the BF cholinergic neurons are not essential to sleep induction. Thus, neither the activity of the BF cholinergic neurons nor the accumulation of AD in the BF during wake is necessary for sleep drive.
The aim of this review is to present some of the recent publications on cannabidiol (CBD; 2), a major non-psychoactive constituent of Cannabis, and to give a general overview. Special emphasis is laid on biochemical and pharmacological advances, and on novel mechanisms recently put forward, to shed light on some of the pharmacological effects that can possibly be rationalized through these mechanisms. The plethora of positive pharmacological effects observed with CBD make this compound a highly attractive therapeutic entity.
Sleep is not the mere absence of wakefulness, but an active state which is finely regulated. The homeostatic facet of sleep-wake regulation is keeping track of changes in 'sleep propensity' (or 'sleep need'), which increases during wakefulness and decreases during sleep. Increased sleep propensity following extended prior wakefulness (sleep deprivation) is counteracted by prolonged sleep duration, but also by enhanced non-rapid-eye-movement (nonREM) sleep intensity as measured by electroencephalographic (EEG) slow-wave activity (SWA, power within approximately 1-4 Hz). This highly reliable regulatory feature of nonREM sleep may be the most important aspect of sleep in relation to its function. The neurochemical mechanisms underlying nonREM sleep homeostasis are poorly understood. Here we provide compelling and convergent evidence that adenosinergic neurotransmission plays a role in nonREM sleep homeostasis in humans. Specifically, a functional polymorphism in the adenosine metabolizing enzyme, adenosine deaminase, contributes to the high inter-individual variability in deep slow-wave sleep duration and intensity. Moreover, the adenosine receptor antagonist, caffeine, potently attenuates the EEG markers of nonREM sleep homeostasis during sleep, as well as during wakefulness. Finally, adenosinergic mechanisms modulate individual vulnerability to the detrimental effects of sleep deprivation on neurobehavioral performance, and EEG indices of disturbed sleep after caffeine consumption. While these convergent findings strongly support an important contribution of adenosine and adenosine receptors to nonREM sleep homeostasis, further research is needed to elucidate the underlying mechanisms that mediate the actions of adenosine on sleep and the sleep EEG.
A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method has been developed for the simultaneous measurement of adenosine (ADE), dopamine (DA), acetylcholine (ACh) and 5-hydroxytryptamine (5-HT) in mouse brain microdialysates. High method sensitivity (LLOQ of 0.05nM) was achieved by optimization of chromatographic and mass spectrometric parameters. The method was fully validated for its sensitivity, selectivity, matrix effect and stability. The LC-MS/MS method was successfully applied to evaluate the effect of the systemic administration of cocaine or amphetamine on the extracellular levels of ADE, DA, ACh and 5-HT in the mouse nucleus accumbens by microdialysis.
This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye-movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye-movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making.
A rapid and effective isocratic chromatographic procedure is successfully developed to determinate methotrexate (MTX) entrapment efficiency (EE) in polymeric nanocapsules using reversed-phase high-performance liquid chromatography. The method employed a RP-C(18) Shimadzu Shim-pack CLC-ODS (150 mm x 4.6 mm, 5 microm) column with mobile phase constituted by a mixture of water-acetonitrile-tetrahydrofuran (65:30:5 v/v/v; pH 3.0) at a flow rate of 0.8 mL/min. The eluate is monitored with a UV detector set at 313 nm. The parameters used in the validation process are: linearity, specificity, precision, accuracy, and limit of quantitation (LOQ). The linearity is evaluated by a calibration curve in the concentration range of 10-50 microg/mL and presented a correlation coefficient of 0.9998. The polymers (PLA or PLA-PEG), oil, and surfactants used in the nanocapsule formulation did not interfere with analysis and the recovery was quantitative. The intra and inter-day assay relative standard deviation were less than 0.72%. Results are satisfactory, and the method proved to be adequate for the determination of methotrexate in nanocapsules formulations.
The major non-psychoactive component of Cannabis sativa, cannabidiol (CBD), displays a plethora of actions including wakefulness. In the present study, we addressed whether perfusing CBD via microdialysis into lateral hypothalamus (LH) during the lights-on period would modify the sleep-wake cycle of rats as well as the contents of dopamine (DA) collected from nucleus accumbens (AcbC). Additionally, we tested whether perfusion of CBD into LH would block the sleep rebound after a sleep deprivation period.
Electroencephalogram and electromyogram electrodes were implanted in rats as well as a guide-cannula aimed to LH or AcbC. CBD perfusion was carried out via cannulae placed into LH whereas contents of DA were collected from AcbC and analyzed using HPLC means.
We found that microdialysis perfusion of CBD (30, 60, or 90 nM) into LH of rat enhances alertness and suppresses sleep. This effect was accompanied with an increase in DA extracellular levels collected from the AcbC. Furthermore, perfusion of CBD into LH after total sleep deprivation prevented the sleep rebound.
These findings enhance the investigation about the neurobiological properties of CBD on sleep modulation.
The actions of cannabidiol (CBD), one of the cannabis constituents, were assessed on the sleep-wakefulness cycle of male Wistar rats.
During acute experiments, single doses of 20 mg/kg CBD decreased slow-wave sleep (SWS) latency. After 40 mg/kg SWS time was significantly increased while wakefulness was decreased. REM sleep was not significantly modified. Following the once-daily injections of 40 mg/kg CBD for a period of 15 days, tolerance developed to all the above-mentioned effects.
Clinical trials with cannabidiol (CBD) in healthy volunteers, isomniacs, and epileptic patients conducted in the authors' laboratory from 1972 up to the present are reviewed. Acute doses of cannabidiol ranging from 10 to 600 mg and chronic administration of 10 mg for 20 days or 3 mg/kg/day for 30 days did not induce psychologic or physical symptoms suggestive of psychotropic or toxic effects; however, several volunteers complained of somnolence. Complementary laboratory tests (EKG, blood pressure, and blood and urine analysis) revealed no sign of toxicity. Doses of 40, 80, and 160 mg cannabidiol were compared to placebo and 5 mg nitrazepam in 15 insomniac volunteers. Subjects receiving 160 mg cannabidiol reported having slept significantly more than those receiving placebo; the volunteers also reported significantly less dream recall; with the three doses of cannabidiol than with placebo. Fifteen patients suffering from secondary generalized epilepsy refractory to known antiepileptic drugs received either 200 to 300 mg cannabidiol daily or placebo for as long as 4.5 months. Seven out of the eight epileptics receiving cannabidiol had improvement of their disease state, whereas only one placebo patient improved.
Cannabis is one of the most widely used drugs throughout the world. The psychoactive constituent of cannabis, delta 9-tetrahydrocannabinol (delta 9-THC), produces a myriad of pharmacological effects in animals and humans. For many decades, the mechanism of action of cannabinoids, compounds which are structurally similar to delta 9-THC, was unknown. Tremendous progress has been made recently in characterizing cannabinoid receptors both centrally and peripherally and in studying the role of second messenger systems at the cellular level. Furthermore, an endogenous ligand, anandamide, for the cannabinoid receptor has been identified. Anandamide is a fatty-acid derived compound that possesses pharmacological properties similar to delta 9-THC. The production of complex behavioral events by cannabinoids is probably mediated by specific cannabinoid receptors and interactions with other neurochemical systems. Cannabis also has great therapeutic potential and has been used for centuries for medicinal purposes. However, cannabinoid-derived drugs on the market today lack specificity and produce many unpleasant side effects, thus limiting therapeutic usefulness. The advent of highly potent analogs and a specific antagonist may make possible the development of compounds that lack undesirable side effects. The advancements in the field of cannabinoid pharmacology should facilitate our understanding of the physiological role of endogenous cannabinoids.
Samples of extracellular fluid from striatum and nucleus accumbens of anaesthetised rats undergoing opiate withdrawal were collected using microdialysis and then analysed for adenosine and its metabolites using high performance liquid chromatography (HPLC) and ultraviolet (UV) detection. Although the amount of adenosine present in the dialysate from either brain region was below the limit of detection by 90 min after probe placement, the metabolites could still be detected. Samples of dialysates collected from the nucleus accumbens contained significantly higher concentrations of hypoxanthine and inosine following naloxone challenge. The data are compatible with the hypothesis that endogenous adenosine might be involved in the expression of the opiate abstinence syndrome.
Previous data suggested that increases in extracellular adenosine in the basal forebrain mediated the sleep-inducing effects of prolonged wakefulness. The present study sought to determine if the state-related changes found in basal forebrain adenosine levels occurred uniformly throughout the brain. In vivo microdialysis sample collection coupled to microbore high-performance liquid chromatography measured extracellular adenosine levels in six brain regions of the cat: basal forebrain, cerebral cortex, thalamus, preoptic area of hypothalamus, dorsal raphe nucleus and pedunculopontine tegmental nucleus. In all these brain regions extracellular adenosine levels showed a similar decline of 15 to 20% during episodes of spontaneous sleep relative to wakefulness. Adenosine levels during non-rapid eye movement sleep did not differ from rapid eye movement sleep. In the course of 6h of sleep deprivation, adenosine levels increased significantly in the cholinergic region of the basal forebrain (to 140% of baseline) and, to a lesser extent in the cortex, but not in the other regions. Following sleep deprivation, basal forebrain adenosine levels declined very slowly, remaining significantly elevated throughout a 3-h period of recovery sleep, but elsewhere levels were either similar to, or lower than, baseline. The site-specific accumulation of adenosine during sleep deprivation suggests a differential regulation of adenosine levels by as yet unidentified mechanisms. Moreover, the unique pattern of sleep-related changes in basal forebrain adenosine level lends strong support to the hypothesis that the sleep-promoting effects of adenosine, as well as the sleepiness associated with prolonged wakefulness, are both mediated by adenosinergic inhibition of a cortically projecting basal forebrain arousal system.
Adenosine is directly linked to the energy metabolism of cells. In the central nervous system an increase in neuronal activity enhances energy consumption as well as extracellular adenosine concentrations. In most brain areas high extracellular adenosine concentrations, through A(1) adenosine receptors, decrease neuronal activity and thus the need for energy. Adenosine seems to act as a direct negative feed-back inhibitor of neuronal activity. Hypoxia and ischemia induce very high extracellular adenosine levels, which may limit further brain damage. In brain areas that regulate cortical vigilance, particularly in the basal forebrain, high extracellular adenosine concentrations, induced by prolonged wakefulness, decrease the activity of presumably cholinergic cells and via this mechanism promote sleep. Our hypothesis is that in the cholinergic basal forebrain prolonged wakefulness induces local energy depletion that generates increases in extracellular adenosine concentrations in this area. In addition to the immediate effects, high extracellular adenosine concentrations also induce intracellular changes in signal transduction and transcription, e.g. increase in A(1) receptor expression and NF-kappaB binding activity. These changes may at least partially mediate the long term effects of prolonged wakefulness. Adenosine may also be a common mediator of the effects of several other sleep-inducing factors.
The effects of cannabis extracts on nocturnal sleep, early-morning performance, memory, and sleepiness were studied in 8 healthy volunteers (4 males, 4 females; 21 to 34 years). The study was double-blind and placebo-controlled with a 4-way crossover design. The 4 treatments were placebo, 15 mg Delta-9-tetrahydrocannabinol (THC), 5 mg THC combined with 5 mg cannabidiol (CBD), and 15 mg THC combined with 15 mg CBD. These were formulated in 50:50 ethanol to propylene glycol and administered using an oromucosal spray during a 30-minute period from 10 pm. The electroencephalogram was recorded during the sleep period (11 pm to 7 am). Performance, sleep latency, and subjective assessments of sleepiness and mood were measured from 8:30 am (10 hours after drug administration). There were no effects of 15 mg THC on nocturnal sleep. With the concomitant administration of the drugs (5 mg THC and 5 mg CBD to 15 mg THC and 15 mg CBD), there was a decrease in stage 3 sleep, and with the higher dose combination, wakefulness was increased. The next day, with 15 mg THC, memory was impaired, sleep latency was reduced, and the subjects reported increased sleepiness and changes in mood. With the lower dose combination, reaction time was faster on the digit recall task, and with the higher dose combination, subjects reported increased sleepiness and changes in mood. Fifteen milligrams THC would appear to be sedative, while 15 mg CBD appears to have alerting properties as it increased awake activity during sleep and counteracted the residual sedative activity of 15 mg THC.
Interactions between the cannabinoid system and the adenosine system were investigated in the myenteric plexus-longitudinal muscle (MPLM) of the guinea-pig ileum.
Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by exogenous adenosine and the adenosine receptor agonist 2-chloroadenosine. These inhibitory effects were reversed by the selective A1 receptor antagonist DPCPX (20 nM).
Preincubation of the MPLM with the cannabinoid receptor agonist CP55,940 (1 nM) or the endogenous cannabinoid ligand anandamide caused a significant leftward shift in the concentration-effect curves to adenosine and 2-chloroadenosine.
Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by the adenosine uptake inhibitor dipyridamole. This inhibition was reversed by DPCPX (20 nM).
Pretreatment with CP55,940 (1 nM) or anandamide (10 μM) significantly reduced the inhibition produced by dipyridamole, an effect which was completely reversed by the selective CB1 receptor ligand SR141716 (100 nM).
Electrically evoked adenosine release, measured in real time by means of adenosine-specific biosensors, was inhibited by CP55,940 (10 nM). This inhibition was blocked when CP55,940 was applied in the presence of SR141716 (100 nM).
These results confirm the presence of presynaptic CB1 and A1 receptors in the guinea-pig MPLM, and suggest that CB1 receptor stimulation reduces electrically-evoked adenosine release. Overall the data raise the possibility that the cannabinoid system plays a role in the modulation of adenosine transmission in the MPLM.
British Journal of Pharmacology (2002) 137, 1298–1304. doi:10.1038/sj.bjp.0704985
Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabidiol (CBD) are two major constituents of Cannabis sativa. Delta(9)-THC modulates sleep, but no clear evidence on the role of CBD is available. In order to determine the effects of CBD on sleep, it was administered intracerebroventricular (icv) in a dose of 10 microg/5 microl at the beginning of either the lights-on or the lights-off period. We found that CBD administered during the lights-on period increased wakefulness (W) and decreased rapid eye movement sleep (REMS). No changes on sleep were observed during the dark phase. Icv injections of CBD (10 microg/5microl) induced an enhancement of c-Fos expression in waking-related brain areas such as hypothalamus and dorsal raphe nucleus (DRD). Microdialysis in unanesthetized rats was carried out to characterize the effects of icv administration of CBD (10 microg/5 microl) on extracellular levels of dopamine (DA) within the nucleus accumbens. CBD induced an increase in DA release. Finally, in order to test if the waking properties of CBD could be blocked by the sleep-inducing endocannabinoid anandamide (ANA), animals received ANA (10 microg/2.5 microl, icv) followed 15 min later by CBD (10 microg/2.5 microl). Results showed that the waking properties of CBD were not blocked by ANA. In conclusion, we found that CBD modulates waking via activation of neurons in the hypothalamus and DRD. Both regions are apparently involved in the generation of alertness. Also, CBD increases DA levels as measured by microdialysis and HPLC procedures. Since CBD induces alertness, it might be of therapeutic value in sleep disorders such as excessive somnolence.
There are significant decrements in sleep with age. These include fragmentation of sleep, increased wake time, decrease in the length of sleep bouts, decrease in the amplitude of the diurnal rhythm of sleep, decrease in rapid eye movement sleep and a profound decrease in electroencephalogram Delta power (0.3-4 Hz). Old rats also have less sleep in response to 12 h-prolonged wakefulness (W) indicating a reduction in sleep drive with age. The mechanism contributing to the decline in sleep with aging is not known but cannot be attributed to loss of neurons implicated in sleep since the numbers of neurons in the ventral lateral preoptic area, a region implicated in generating sleep, is similar between young (3.5 months) and old (21.5 months) rats. One possibility for the reduced sleep drive with age is that sleep-wake active neurons may be stimulated less as a result of a decline in endogenous sleep factors. Here, we test this hypothesis by focusing on the purine, adenosine (AD), one such sleep factor that increases after prolonged W. In experiment 1, microdialysis measurements of AD in the basal forebrain at 1 h intervals reveal that old (21.5 months) rats have more extracellular levels of AD compared with young rats across the 24 h diurnal cycle. In experiment 2, old rats kept awake for 6 h (first half of lights-on period) accumulated more AD compared with young rats. If old rats have more AD then why do they sleep less? To investigate whether changes in sensitivity of the AD receptor contribute to the decline in sleep, experiments 3 and 4 determined that for the same concentration of AD or the AD receptor 1 agonist, cyclohexyladenosine, old rats have less sleep compared with young rats. We conclude that even though old rats have more AD, a reduction in the sensitivity of the AD receptor to the ligand does not transduce the AD signal at the same strength as in young rats and may be a contributing factor to the decline in sleep drive in the elderly.
The Rat Brain in Stereotaxic Coordinates, fourth ed Adenosine and sleep
- G Paxinos
- C Watson
Paxinos, G., Watson, C., 2005. The Rat Brain in Stereotaxic Coordinates, fourth ed. Academic Press, San Diego, CA. Porkka-Heiskanen, T., Alanko, L., Kalinchuk, A., Stenberg, D., 2002. Adenosine and sleep. Sleep Med. Rev. 6, 321–332.
Cannabidiolrecent advances
- R Mechoulam
- M Peters
- E Murillo-Rodríguez
- L O Hanus
Mechoulam, R., Peters, M., Murillo-Rodríguez, E., Hanus, L.O., 2007. Cannabidiolrecent advances. Chem. Biodivers. 4, 1678-1692.