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Cannabinoids inhibit the synaptic uptake of adenosine and dopamine in the rat and mouse striatum

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... A study conducted on intact rat striatal synaptosomes identified various modulatory mechanisms that cannabinoids may execute on the reuptake of dopamine, glutamate, and adenosine (Pandolfo et al., 2011). Specifically, CBD has shown a low capacity for inhibiting dopamine reuptake (IC50 16.5 µM), a finding similar to that reported by Poddar and Dewey 1980, who found that, in striatum synaptosomes, high concentrations of CBD were needed to produce an inhibitory effect on dopamine recapture. ...
... meaning that CBD treatment in the latter stages of the disease is likely to be ineffective. Furthermore, CBD had potent inhibitory effects on adenosine reuptake (IC50 3.5 µM) (Pandolfo et al., 2011), which may explain its neuromodulatory activity via the expression of the A2A receptors in the BG circuit (Schiffmann et al., 2007). The A2A receptor has been shown to be widely expressed in the striatopallidal pathway, in presynaptic and postsynaptic GABAergic neurons (Rosin et al., 2003;Diao et al., 2017). ...
... Cannabidiol has no psychoactive effects and has shown encouraging results in preclinical and clinical trials conducted on different neurodegenerative diseases. It is also a multi-target drug, as, in addition to acting on the ECS, it can act on the serotonin, adenosine, dopamine, and opioid receptors (Russo et al., 2005;Carrier et al., 2006;Kathmann et al., 2006;Thomas et al., 2007;Pandolfo et al., 2011;Linge et al., 2016;Sonego et al., 2018). As most of the aforementioned CBD-activated receptors are coupled to an inhibitory G protein, they are capable of acting as neuromodulators, given that they regulate the release of other neurotransmitters. ...
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The phytocannabinoids of Cannabis sativa L. have, since ancient times, been proposed as a pharmacological alternative for treating various central nervous system (CNS) disorders. Interestingly, cannabinoid receptors (CBRs) are highly expressed in the basal ganglia (BG) circuit of both animals and humans. The BG are subcortical structures that regulate the initiation, execution, and orientation of movement. CBRs regulate dopaminergic transmission in the nigro-striatal pathway and, thus, the BG circuit also. The functioning of the BG is affected in pathologies related to movement disorders, especially those occurring in Parkinson’s disease (PD), which produces motor and non-motor symptoms that involving GABAergic, glutamatergic, and dopaminergic neural networks. To date, the most effective medication for PD is levodopa (l-DOPA); however, long-term levodopa treatment causes a type of long-term dyskinesias, l-DOPA-induced dyskinesias (LIDs). With neuromodulation offering a novel treatment strategy for PD patients, research has focused on the endocannabinoid system (ECS), as it participates in the physiological neuromodulation of the BG in order to control movement. CBRs have been shown to inhibit neurotransmitter release, while endocannabinoids (eCBs) play a key role in the synaptic regulation of the BG. In the past decade, cannabidiol (CBD), a non-psychotropic phytocannabinoid, has been shown to have compensatory effects both on the ECS and as a neuromodulator and neuroprotector in models such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and reserpine, as well as other PD models. Although the CBD-induced neuroprotection observed in animal models of PD has been attributed to the activation of the CB1 receptor, recent research conducted at a molecular level has proposed that CBD is capable of activating other receptors, such as CB2 and the TRPV-1 receptor, both of which are expressed in the dopaminergic neurons of the nigro-striatal pathway. These findings open new lines of scientific inquiry into the effects of CBD at the level of neural communication. Cannabidiol activates the PPARγ, GPR55, GPR3, GPR6, GPR12, and GPR18 receptors, causing a variety of biochemical, molecular, and behavioral effects due to the broad range of receptors it activates in the CNS. Given the low number of pharmacological treatment alternatives for PD currently available, the search for molecules with the therapeutic potential to improve neuronal communication is crucial. Therefore, the investigation of CBD and the mechanisms involved in its function is required in order to ascertain whether receptor activation could be a treatment alternative for both PD and LID.
... Authors also found that the effect was not attenuated by Pertussis toxin, excluding the involvement of CB 1, CB2 or GPR55 receptors, but not excluding that of TRPV1 receptors. Other authors also reported an inhibition of the dopamine transporter by different cannabinoid ligands in the rodent striatum (Price et al., 2007;Pandolfo et al., 2011). The inhibition was seen with the non-selective cannabinoid agonists WIN55,212-2 and O-2545, and also with cannabidiol and NADA, but not with anandamide and 2-arachidonoyl glycerol (Pandolfo et al., 2011). ...
... Other authors also reported an inhibition of the dopamine transporter by different cannabinoid ligands in the rodent striatum (Price et al., 2007;Pandolfo et al., 2011). The inhibition was seen with the non-selective cannabinoid agonists WIN55,212-2 and O-2545, and also with cannabidiol and NADA, but not with anandamide and 2-arachidonoyl glycerol (Pandolfo et al., 2011). The effect was also seen with various CB1 receptor antagonists/inverse agonists such as AM251 (Pandolfo et al., 2011). ...
... The inhibition was seen with the non-selective cannabinoid agonists WIN55,212-2 and O-2545, and also with cannabidiol and NADA, but not with anandamide and 2-arachidonoyl glycerol (Pandolfo et al., 2011). The effect was also seen with various CB1 receptor antagonists/inverse agonists such as AM251 (Pandolfo et al., 2011). As expected, authors concluded that these effects were likely to be CB1 receptorindependent (Pandolfo et al., 2011). ...
Article
Endocannabinoids and their receptors play a modulatory role in the control of dopamine transmission at the basal ganglia. However, this influence is generally indirect and exerted through the modulation of GABA and glutamate inputs received by nigrostriatal dopaminergic neurons, which lack of CB1 receptors although may produce endocannabinoids. Additional evidence suggest that CB2 receptors may be located in nigrostriatal dopaminergic neurons, as well as that certain eicosanoid-related cannabinoids may directly activate TRPV1 receptors, which have been found in nigrostriatal dopaminergic neurons, thus allowing in both cases a direct regulation of dopamine transmission by specific cannabinoids. In addition, CB1 receptors form heteromers with dopaminergic receptors which represent another way to make possible a direct interaction between both systems, in this case at the postsynaptic level. Through these direct mechanisms or through indirect mechanisms involving GABA or glutamate neurons, cannabinoids may interact with dopamine transmission in the basal ganglia and this likely has an important influence on dopamine-related functions in these structures (i.e. control of movement) and, particularly, on different pathologies affecting these processes, in particular, Parkinson's disease, but also dyskinesia, dystonia and other pathological conditions. The present review will address the current literature supporting these cannabinoid-dopamine interactions at the basal ganglia, with emphasis in aspects dealing with the physiopathological consequences of these interactions. This article is protected by copyright. All rights reserved.
... With regard to dopamine transport, further studies showed a dose-dependent reduction in dopamine uptake following application of CBD (0.5-100.0 μM; IC 50 = 16.2 μM) in rat striatal synaptosomes, consistent with a previous study (Table 4) [105]. Glutamate uptake was again inhibited in a dose-dependent manner following application of CBD (1-100 μM) to rat striatal synaptosomes. ...
... Glutamate uptake was again inhibited in a dose-dependent manner following application of CBD (1-100 μM) to rat striatal synaptosomes. However, unlike CBD's effect on dopamine uptake, half maximal inhibition was achieved at the higher concentration of 43.8 μM [105]. ...
... CBD inhibits the uptake of glutamate, dopamine, and adenosine, but only at high micromolar concentrations [105]. Impaired glutamate uptake has been reported in transgenic rodent models of HD, but the effect of this on motor function has not been determined [176]. ...
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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excluding unlikely and implausible targets, the remaining molecular targets of CBD with plausible evidence for involvement in therapeutic effects in neurological disorders (e.g., voltage-dependent anion channel 1, G protein-coupled receptor 55, CaV3.x, etc.) are associated with either the regulation of, or responses to changes in, intracellular calcium levels. While no causal proof yet exists for CBD's effects at these targets, they represent the most probable for such investigations and should be prioritized in further studies of CBD's therapeutic mechanism of action.
... In the case of adult dopaminergic transmission, it has been observed that an acute systemic administration of CB1 agonists such as WIN55212-2 produces an increase in dopamine extracellular levels in the NAc (Tanda et al., 1997) and dorsolateral striatum (DLS) (Polissidis et al., 2014(Polissidis et al., , 2013. Also, the acute administration of WIN55212-2 decreases the activity of the DA transporter (DAT) in the DS of adult rodents (Pandolfo et al., 2011;Price et al., 2007). However, the effects of cannabinoids on DA release and DA uptake in the DS during adolescence remains to be addressed. ...
... Interestingly, the inhibitory effect of WIN55212-2 on DA uptake has been shown independent of CB1-R activation (Price et al., 2007). In fact, it has been proposed that WIN55212-2 interacts directly with the DAT protein (Pandolfo et al., 2011;Price et al., 2007;Steffens and Feuerstein, 2004). Whether a similar mechanism than the one observed in adult rats underlies an inhibitory effect of WIN55212-2 in DA uptake in adolescent rats remains to be addressed. ...
... Evi dence in the literature points to the fact that CBD inhibits the reuptake of adenosine. [6,7,[42][43][44] Adenosine normally acts as a neuroprotective agent in the central nervous system, and its levels usually increase under conditions of stress. Earlier I alluded to the fact that the ECS plays a role in modulating the nervous system responses to stress. ...
... Adenosine action via the adenosine A1 receptors opens K + channels to hyperpolarise neurons and thereby reduce their excitability, which would be an obvious advantage in epilepsy. [43] Via the same receptor, adenosine can also inhibit the N-type voltagegated Ca 2+ channel to inhibit the release of glutamate, which normally increases the excitability of neuronal networks. [44] ...
Article
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The compounds present in cannabis have been in use for both recreational and medicinal purposes for many centuries. Changes in the legislation in South Africa have led to an increase in the number of people interested in using these compounds for self-medication. Many of them may approach their general practitioner as the first source of information about possible therapeutic effects. It is important that medical professionals are able to give patients the correct information. Cannabidiol (CBD) is one of the main compounds in cannabis plants, and there is evidence that it can successfully treat certain patients with epilepsy. This review looks at the most recent evidence on the use of CBD in the treatment of epilepsy and explores the mechanisms behind these beneficial effects.
... Below we will discuss an additional level of interaction between the two neuromodulator systems, namely that D 2 R activation increases endocannabinoid tone in the brain [715,716]. Yet another unexpected form of cannabinoid-dopamine interaction is worth mentioning: in the low micromolar range, cannabinoid receptor agonists and antagonists including CBD can inhibit the dopamine transporter (DAT) of the rat and the mouse, independently from cannabinoid receptors [717][718][719]. This cross-sensitivity between DAT and cannabinoids is bidirectional, because many DAT inhibitors including cocaine is a PAM at the CB 1 R [407]. ...
... The previously detailed off-target actions at opioid receptors are not exceptional: phytocannabinoids, endocannabinoids and other synthetic cannabinoid ligands are notorious for producing diverse off-target effects in the micromolar range [381,390,391,509,719,[978][979][980][981][982][983] with unclear (patho)physiological significance. These must be taken into consideration, and whenever possible, cannabinoids should be used at the concentration not greater than 1 µM in vitro. ...
Article
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Background & objective: Cannabis is one of the earliest cultivated plants. Cannabis of industrial utility and culinary value is generally termed as hemp. Conversely, cannabis that is bred for medical, spiritual and recreational purposes is called marijuana. The female marijuana plant produces a significant quantity of bio- and psychoactive phytocannabinoids, which regained the spotlight with the discovery of the endocannabinoid system of the animals in the early 90's. Nevertheless, marijuana is surrounded by controversies, debates and misconceptions related to its taxonomic classification, forensic identification, medical potential, legalization and its long-term health consequences. Method: In the first part, we provide an in-depth review of the botany and taxonomy of Cannabis. We then overview the biosynthesis of phytocannabinoids within the glandular trichomes with emphasis on the role of peculiar plastids in the production of the secreted material. We also compile the analytical methods used to determine the phytocannabinoid composition of glandular trichomes. In the second part, we revisit the psychobiology and molecular medicine of marijuana. Results & conclusion: We summarize our current knowledge on the recreational use of cannabis with respect to the modes of consumption, short-term effects, chronic health consequences and cannabis use disorder. Next, we overview the molecular targets of a dozen major and minor bioactive cannabinoids in the body. This helps us introduce the endocannabinoid system in an unprecedented detail: its up-todate molecular biology, pharmacology, physiology and medical significance, and beyond. In conclusion, we offer an unbiased survey about cannabis to help better weigh its medical value versus the associated risks.
... In cellular uptake assays, CBD (1-10 mol/L) inhibits the uptake and metabolism of anandamide, indirectly enhancing endocannabinoid transmission (Bisogno et al., 2001;Leweke et al., 2012). CBD has also been shown to inhibit noradrenaline, dopamine, serotonin, gamma-aminobutyric acid (GABA), and adenosine uptake in striatal tissue at concentrations ranging from 1-17 mol/L (Pandolfo et al., 2011;Pertwee, 2005). Finally, receptor binding, [ 35 S]GTP ␥S, and cAMP assays have found that at higher concentrations (Ͼ10 mol/L), CBD binds to and increases the activity of the 5-hydroxytryptamine 1A serotoninergic (5-HT 1A ) receptor, and allosterically modulatesand ␦-opioid receptors (Kathmann, Flau, Redmer, Tränkle, & Schlicker, 2006;Russo, Burnett, Hall, & Parker, 2005). ...
... This possibility of alcohol reward reduction could be tested in a CPP paradigm. Because there is evidence that CBD inhibits dopamine uptake (Pandolfo et al., 2011), one important consideration is whether CBD in itself is rewarding, negating the need to obtain reward by consumption of alcohol. This possibility, however, is unlikely, given that CBD has not been found to exhibit reinforcing properties in intracranial self-stimulation and CPP paradigms; in short, it is nonreinforcing with no apparent abuse liability (Katsidoni, Anagnostou, & Panagis, 2013;Parker, Burton, Sorge, Yakiwchuk, & Mechoulam, 2004;Vann et al., 2008). ...
Article
Increased access to medicinal and recreational cannabis will be accompanied by greater exposure to its chemical constituents, including Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), the primary nonpsychoactive compound. Increasing attention has focused on CBD, in part, due to its potential therapeutic properties. Relatively little is known about how CBD might interact with other commonly used drugs. While a number of studies have explored the influence of cannabis or Δ9-THC on alcohol consumption and treatment outcomes, few have examined the effects of CBD on alcohol-related outcomes. This article reviews preclinical and human studies examining the effects of CBD administration on alcohol responses. Preliminary preclinical results suggest that CBD can attenuate alcohol consumption and potentially protect against certain harmful effects of alcohol, such as liver and brain damage. Also reviewed herein are the few existing studies involving CBD and alcohol coadministration in humans. The paucity of such studies precludes any definitive conclusions relating to CBD-alcohol interactions. Effects of CBD on alcohol use and potential therapeutic implications for alcohol use disorder are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
... Those complementary mechanisms of action proposed to underlie CBD action could explain some controversial results, such as the indirect agonistic effect on adenosine receptors, especially A 2 receptors, by increasing adenosine levels as a response to nucleoside transport inhibition (Carrier et al., 2006;Liou et al., 2008). Also, endocannabinoids have the same potential to block adenosine transporters as the known inhibitor of nucleoside transporters, dipyridamole (Pandolfo et al., 2011). Another interaction proposed between adenosine and cannabinoids is the existence of A 2A -CB1 receptor heterodimerization, which has been demonstrated by means of bioluminescence resonance energy transfer (BRET) techniques (Carriba et al., 2007;Ferré et al., 2010). ...
... Endocannabinoids have been implicated to affect neurotransmission mediated by glutamate through pre-and post-synaptic mechanisms involving CB1 receptor activation (Gerdeman and Lovinger, 2001;Huang et al., 2001), while no information is available for specific CBD effects. On the other hand, CBD is able to reduce glutamate reuptake in striatal synaptosomes of rats just in the higher doses tested (30-100 μM) by Pandolfo et al. (2011). Additionally, glutamate neurotransmission could be enhanced by CBD inhibition of nucleoside transport, increasing adenosine extracellular levels and action on facilitative A 2A adenosine receptors, as demonstrated in previous works (Carrier et al., 2006). ...
Article
Cannabidiol (CBD) has been investigated in a wide spectrum of clinical approaches due to its psychopharmacological properties. CBD has low affinity for cannabinoid neuroreceptors and agonistic properties to 5-HT receptors. An interaction between cannabinoid and purinergic receptor systems has been proposed. The purpose of this study is to evaluate CBD properties on memory behavioral and locomotor parameters and the effects of pre-treatment of adenosine receptor blockers on CBD impacts on memory using adult zebrafish. CBD (0.1, 0.5, 5, and 10mg/kg) was tested in the avoidance inhibitory paradigm and anxiety task. We analyzed the effect of a long-term caffeine pre-treatment (~20mg/L - four months). Also, acute block of adenosine receptors was performed in co-administration with CBD exposure in the memory assessment. CBD promoted an inverted U-shaped dose-response curve in the anxiety task; in the memory assessment, CBD in the dose of 5mg/Kg promoted the strongest effects without interfering with social and aggressive behavior. Caffeine treatment was able to prevent CBD (5mg/kg) effects on memory when CBD was given after the training session. CBD effects on memory were partially prevented by co-treatment with a specific A2A adenosine receptor antagonist when given prior to or after the training session, while CBD effects after the training session were fully prevented by adenosine A1 receptor antagonist. These results indicated that zebrafish have responses to CBD anxiolytic properties that are comparable to other animal models, and high doses changed memory retention in a way dependent on adenosine. Copyright © 2015 Elsevier Inc. All rights reserved.
... Perhaps the largest body of evidence pertains to the modulation and activation of 5hydroxytryptamine 1A serotoninergic receptors [29][30][31][32][33][34][35]. CBD also has low potency for inhibiting the uptake of striatal dopamine [36]; it modulates allosterically μ and δ opioid receptors [37] and enhances adenosine signaling through uptake inhibition [36,38]. Although more studies are needed to further understand the impact of CBD on glutamatergic neurotransmission, its protective effects on glutamate toxicity and its pharmacologic interaction with ketamine [39,40], an Nmethyl-D-aspartate receptor (NMDA) antagonist, are also well documented. ...
... Perhaps the largest body of evidence pertains to the modulation and activation of 5hydroxytryptamine 1A serotoninergic receptors [29][30][31][32][33][34][35]. CBD also has low potency for inhibiting the uptake of striatal dopamine [36]; it modulates allosterically μ and δ opioid receptors [37] and enhances adenosine signaling through uptake inhibition [36,38]. Although more studies are needed to further understand the impact of CBD on glutamatergic neurotransmission, its protective effects on glutamate toxicity and its pharmacologic interaction with ketamine [39,40], an Nmethyl-D-aspartate receptor (NMDA) antagonist, are also well documented. ...
Article
Multiple cannabinoids derived from the marijuana plant have potential therapeutic benefits but most have not been well investigated, despite the widespread legalization of medical marijuana in the USA and other countries. Therapeutic indications will depend on determinations as to which of the multiple cannabinoids, and other biologically active chemicals that are present in the marijuana plant, can be developed to treat specific symptoms and/or diseases. Such insights are particularly critical for addiction disorders, where different phytocannabinoids appear to induce opposing actions that can confound the development of treatment interventions. Whereas Δ(9)-tetracannabinol has been well documented to be rewarding and to enhance sensitivity to other drugs, cannabidiol (CBD), in contrast, appears to have low reinforcing properties with limited abuse potential and to inhibit drug-seeking behavior. Other considerations such as CBD's anxiolytic properties and minimal adverse side effects also support its potential viability as a treatment option for a variety of symptoms associated with drug addiction. However, significant research is still needed as CBD investigations published to date primarily relate to its effects on opioid drugs, and CBD's efficacy at different phases of the abuse cycle for different classes of addictive substances remain largely understudied. Our paper provides an overview of preclinical animal and human clinical investigations, and presents preliminary clinical data that collectively sets a strong foundation in support of the further exploration of CBD as a therapeutic intervention against opioid relapse. As the legal landscape for medical marijuana unfolds, it is important to distinguish it from "medical CBD" and other specific cannabinoids, that can more appropriately be used to maximize the medicinal potential of the marijuana plant.
... Since 90% of dopaminergic neurons die in the late stage of PD [42], CBD treatment is likely to be ineffective through inhibiting dopamine recapture in the striatum synaptosomes [43], a model in the early stage of PD was adopted in this study to evaluate the therapeutic effect of CBD on PD. It has previously been proven that cannabis has a beneficial effect on tremor and stiffness, a minor effect on bradykinesia, and a tendency to improve posture, all of which are motor symptoms of PD [44]. ...
... As CBD is a lipophilic structure, it can cross the blood-brain barrier and has neuromodulation and protection effects on specific areas of the CNS [47]. Additionally, cannabinoids may execute on the reuptake of glutamate in the brain [43]. A statistically significant alteration of glutamate level was identified in blood samples as well from PD [48]. ...
Article
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Parkinson’s disease (PD) is a common neurodegenerative disease characterized by a disorder of the dopaminergic system in the midbrain, causing classical PD motor symptoms. The therapeutic effect of cannabidiol (CBD) on PD has been a research frontier in recent years. However, the pathogenesis of PD and the therapeutic mechanism of cannabinoid remain unclear. To further study the causes of PD and the effect of CBD on PD, we exposed the PD transgenic mouse model to CBD and then estimated the motorial and postural coordination through a modified swim test. Afterwards, the mechanism was investigated via the histopathology of substantia nigra and the gut-brain metabolic analysis in the approach of UHPLC-TOF-MS. The results showed that CBD significantly improved motor deficits of PD model and protected the substantia nigra area. The metabolic function of fatty acid biosynthesis, arginine biosynthesis/metabolism, butanoate (ketone body) metabolism, β-alanine metabolism, and pantothenate/CoA biosynthesis was highlighted in the pathological and therapeutic process along the gut-brain axis. In conclusion, CBD could attenuate PD via the neuroprotective effect on the midbrain. The attenuation of the central nervous system in turn improved motor performance of PD, which might be partially induced by the metabolic interaction between the gut-brain. In view of gut-brain metabolomics, the mechanism of PD pathogenesis and the effect of CBD on PD are highly related to the biosynthesis and metabolism of energy and essential substance.
... CBD also regulates several transporters, enzymes, and metabolic pathways that are common to Δ9-THC and endocannabinoid signaling. CBD inhibits uptake of adenosine by blocking the equilibrative nucleoside transporter [118,119]. Increased levels of adenosine activate A2 receptors, which regulate striatal CB 1 Rs [120]. At high micromolar [73] levels, CBD also inhibits the uptake and enzymatic degradation of anandamide via FAAH, elevating anandamide extracellular concentrations [121]. ...
Article
The force of the recent explosion of largely unproven and unregulated cannabis-based preparations on medical therapeutics may have its greatest impact in the field of neurology. Paradoxically, for 10 millennia this plant has been an integral part of human cultivation, where it was used for its fibers long before its pharmacological properties. With regard to the latter, cannabis was well known to healers from China and India thousands of years ago; Greek and Roman doctors during classic times; Arab doctors during the Middle Ages; Victorian and Continental physicians in the nineteenth century; American doctors during the early twentieth century; and English doctors until 1971 when a variety of nonevidence-based remedies were removed from the British Pharmaceutical Codex. However, cannabis-based or cannabis-derived medicines have been almost entirely absent from American medicine and barely present in European and Asian pharmacopeias during the twenty-first century [1].
... CBD also regulates several transporters, enzymes, and metabolic pathways that are common to Δ9-THC and endocannabinoid signaling. CBD inhibits uptake of adenosine by blocking the equilibrative nucleoside transporter [118,119]. Increased levels of adenosine activate A2 receptors, which regulate striatal CB 1 Rs [120]. At high micromolar [73] levels, CBD also inhibits the uptake and enzymatic degradation of anandamide via FAAH, elevating anandamide extracellular concentrations [121]. ...
Article
Erratum to: Neurotherapeutics DOI: 10.1007/s13311-015-0388-0 In the sixth paragraph, the second sentence should read: Government should help to protect people from harm—whether the harm comes from spending money on products that do not deliver on their promise or have the potential to cause adverse effects that do not outweigh their beneficial effects.
... The plausible and implausible CBD's molecular targets as well as the potential pharmacological effects of CBD in neurological disorders including epilepsy have been recently reviewed by Ibeas Bih et al. [23]. Briefly, regarding its anticonvulsant activity, it has been reported that CBD might influence neuronal hyperexcitability by several mechanisms: (1) reducing the synaptic release of glutamate as a result of its antagonism on the G protein-coupled receptor (GPR) 55; (2) activating 5-HT 1a receptors [27,28]; (3) stimulating and desensitizing transient receptor potential of ankyrin type 1 (TRPA1) channel; (4) stimulating and desensitizing transient receptor potential of vanilloid type 1 (TRPV1) and 2 (TRPV2) channels [29,30]; (5) inhibiting the synaptic uptake of noradrenaline, GABA, adenosine as well as dopamine [31,32]; (6) stimulating the activity of 3 and 1 glycine receptors [33,34]. Likewise, other potential targets of CBD have been hypothesized , however, for some of them including; voltage-dependent anion channel 1 (VDAC1), peroxisome proliferator-activated receptor (PPAR-), nitric oxide (NO), cyclooxygenase (COX), tumour necrosis factor (TNF), fatty acid amide hydrolase (FAAH) and G protein-coupled receptor (GPR) 18 the CBD's potency on these molecular targets as well as the validity of the target in epilepsy needs to be better clarified by further studies. ...
Article
Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remains still poor. Unfortunately, besides several advantages, these new AEDs have not satisfactorily reduced the number of refractory patients. Therefore, the need for different other therapeutic options to manage epilepsy is still a current issue. To this purpose, emphasis has been given to phytocannabinoids, which have been medicinally used since ancient time in the treatment of neurological disorders including epilepsy. In particular, the nonpsychoactive compound cannabidiol (CBD) has shown anticonvulsant properties, both in preclinical and clinical studies, with a yet not completely clarified mechanism of action. However, it should be made clear that most phytocannabinoids do not act on the endocannabinoid system as in the case of CBD. In in vivo preclinical studies, CBD has shown significant anticonvulsant effects mainly in acute animal models of seizures, whereas restricted data exist in chronic models of epilepsy as well as in animal models of epileptogenesis. Likewise, clinical evidence seem to indicate that CBD is able to manage epilepsy both in adults and children affected by refractory seizures, with a favourable side effect profile. However, to date, clinical trials are both qualitatively and numerically limited, thus yet inconsistent. Therefore, further preclinical and clinical studies are undoubtedly needed to better evaluate the potential therapeutic profile of CBD in epilepsy, although the actually available data is promising.
... CBD might act on or modify the function of several receptors, including CB 1 , CB 2 , G-protein-coupled receptor 55, TRPV 1 , and TRPV 2 , transient receptor potential melastin type 8 (TRPM 8 ), and ankyrin type 1 (TRPA 1 ) (Bisogno et al., 2001;De Petrocellis et al., 2011;Russo et al., 2005;Thomas et al., 2007). It could also inhibit the FAAH enzyme and the adenosine transporter (Bisogno et al. 2001;Pandolfo et al., 2011), indirectly increasing the levels of endocannabinoids or adenosine. Additionally, some CBD effects involve intracellular pathways or receptors, such as peroxisome proliferator-activated receptor γ (PPARγ), that play fundamental roles in cell survival (Esposito et al., 2011). ...
Chapter
Cannabidiol (CBD), the major nonpsychotomimetic compound present in the Cannabis sativa plant, is a promising drug to treat several neuropsychiatric and nonneuropsychiatric disorders. Although its precise mechanism of action is unknown, CBD's effects seem to involve various neurotransmitter and transduction signaling systems. It acts on CB1, CB2, GPR55, and TRPV1 receptors and inhibits the adenosine transporter and the fatty acid amide hydrolase enzyme, indirectly increasing the levels of endocannabinoids. In addition, several studies indicate that one of the main CBD targets is the serotonergic system, particularly 5HT1A receptors. This chapter critically discusses the evidence supporting the proposal that facilitation of 5HT1A-mediated neurotransmission is involved in the acute anxiolytic, antidepressant, neuroprotective, antinausea, and motor control effects of CBD. Although the mechanisms responsible for this facilitation are still unclear, they could involve allosteric interactions with the receptor binding site and/or interference with intracellular pathways.
... CBD also regulates several transporters, enzymes, and metabolic pathways that are common to Δ9-THC and endocannabinoid signaling. CBD inhibits uptake of adenosine by blocking the equilibrative nucleoside transporter [118,119]. Increased levels of adenosine activate A2 receptors, which regulate striatal CB 1 Rs [120]. At high micromolar [73] levels, CBD also inhibits the uptake and enzymatic degradation of anandamide via FAAH, elevating anandamide extracellular concentrations [121]. ...
Article
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Cannabis has been used for centuries to treat seizures. Recent anecdotal reports, accumulating animal model data, and mechanistic insights have raised interest in cannabis-based antiepileptic therapies. In this study, we review current understanding of the endocannabinoid system, characterize the pro- and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and highlight scientific evidence from pre-clinical and clinical trials of cannabinoids in epilepsy. These studies suggest that CBD avoids the psychoactive effects of the endocannabinoid system to provide a well-tolerated, promising therapeutic for the treatment of seizures, while whole-plant cannabis can both contribute to and reduce seizures. Finally, we discuss results from a new multicenter, open-label study using CBD in a population with treatment-resistant epilepsy. In all, we seek to evaluate our current understanding of cannabinoids in epilepsy and guide future basic science and clinical studies.
... The possible molecular mechanisms by which CBD may influence neuronal hyperexcitability are: 1) activation of 5-HT 1a receptors [42,43]; 2) reduction of the synaptic release of glutamate antagonizing G protein-coupled receptor (GPR) 55); 3) stimulation and desensitization of transient receptor potential of vanilloid type 1 (TRPV1) and 2 (TRPV2) channels [44,45]; 4) inhibition of the synaptic uptake of GABA, noradrenaline, adenosine as well as dopamine [46,47]; 5) stimulation of 3 and 1 glycine receptors [48,49]; 6) stimulation and desensitization transient receptor potential of ankyrin type 1 (TRPA1) channel. ...
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Background: Several antiepileptic drugs (AEDs), about 25, are currently clinically available for the treatment of patients with epilepsy. Despite this armamentarium and the many recently introduced AEDs, no major advances have been achieved considering the number of drug resistant patients, while many benefits have been indeed obtained for other clinical outcomes (e.g. better tolerability, less interactions). Cannabinoids have long been studied for their potential therapeutical use and more recently phytocannabinoids have been considered a valuable tool for the treatment of several neurological disorders including epilepsy. Among this wide class, the most studied is cannabidiol (CBD) considering its lack of psychotropic effects and its anticonvulsant properties. Objective: Analyse the currently available literature on CBD also in light of other data on phytocannabinoids, reviewing data spanning from the mechanism of action, pharmacokinetic to clinical evidences. Results: Several preclinical studies have tried to understand the mechanism of action of CBD, which still remains largely not understood. CBD has shown significant anticonvulsant effects mainly in acute animal models of seizures; beneficial effects were reported also in animal models of epileptogenesis and chronic models of epilepsy, although not substantial. In contrast, data coming from some studies raise questions on the effects of other cannabinoids and above all marijuana. Conclusions: There is indeed sufficient supporting data for clinical development and important antiepileptic effects and the currently ongoing clinical studies will permit the real usefulness of CBD and possibly other cannabinoids. Undoubtedly, several issues also need to be addressed in the next future (e.g. better pharmacokinetic profiling). Finally, shading light on the mechanism of action and the study of other cannabinoids might represent an advantage for future developments.
... Cannabidiol interacts with neurotransmitter systems that are critical for the effects of both types of drugs. For example, cannabidiol can allosterically modulate μ and δ opioid receptors (Kathmann et al., 2006), and also has a low potency for inhibiting uptake in striatal dopamine synapses (Pandolfo et al., 2011). Ren et al. (2009) demonstrated a reversal of the reduction in the expression of NAc AMPA glutamate receptor GluA1 subunits in heroin-trained rats following treatment with cannabidiol. ...
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Cannabidiol is a non-psychoactive compound that is the second most abundant component of cannabis. It has been shown to have a potential therapeutic value for a wide range of disorders, including anxiety, psychosis, and depression. Recently, it was suggested that cannabidiol might be a potential treatment for heroin craving and relapse. Here we investigated the effects of an acute treatment with cannabidiol on cocaine self-administration and cue-induced cocaine seeking in rats. Rats were trained to press a lever to self-administer cocaine (0.5 mg/kg/infusion), first under a fixed interval 20 s (FI-20 s) and then under a progressive ratio (PR) schedule of reinforcement. Cocaine self-administration under a PR schedule of reinforcement was not attenuated by cannabidiol injections (5.0 mg/kg and 10.0 mg/kg; i.p.) when tested 30 min and 24 h after treatment. Cannabidiol treatment (5.0 mg/kg or 10.0 mg/kg) also did not attenuate cue-induced cocaine seeking in rats after a withdrawal period of 14 days. In contrast, treatment with cannabidiol (10.0 mg/kg; i.p.) resulted in a statistically significant anxiolytic effect in the elevated plus-maze. Our findings suggest that, under the conditions described here, an acute cannabidiol treatment has a minimal effect on a rat model of cocaine intake and relapse.
... Recently, it has been reported that CBD might influence neuronal hyperexcitability by several mechanisms: decreasing the synaptic release of glutamate as a result of its antagonism on the Gprotein-coupled receptor 55 (GPR55); activating 5-HT1a receptors [53,54]; stimulating and desensitizing transient receptor potential of ankyrin type 1 (TRPA1) and of vanilloid type 1 (TRPV1) and 2 (TRPV2) channels [55,56]; inhibiting the synaptic uptake of noradrenaline, GABA, adenosine as well as dopamine [57], and stimulating the activity of α3 and α1 glycine receptors [58,59]. Moreover, further potential targets of CBD have been hypothesized: voltage-dependent anion channel 1 (VDAC1), nitric oxide (NO), peroxisome proliferator-activated receptor γ (PPAR-γ), tumor necrosis factor (TNF), cyclooxygenase (COX), fatty acid amide hydrolase (FAAH) and G-protein-coupled receptor (GPR) 18 [50]. ...
Article
Background: Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remain unsatisfactory. In addition, whilst several antiepileptic drugs (AEDs) have been approved and consequently marketed in recent years, little is known about their long-term safety and tolerability. Availability of the newest AEDs, characterized by improved pharmacokinetic profiles, has positively impacted the treatment approach for patients with partial seizures in clinical practice. However, the main cause of treatment failure is still poor patient compliance due to the occurrence of adverse drug reactions (ADRs) that lead to treatment withdrawal in about 25% of cases before achieving maximal efficacy, and is associated with increasing health care costs. Methods: In this Review, we conducted an online database search using Medline, PubMed, Embase, and the Cochrane Online Library to review the available studies highlighting the clinical relevance of side effects, pharmacological interactions, safety and tolerability of the newest AEDs: Brivaracetam (BRV), Cannabidiol (CBD), Eslicarbazepine acetate (ESL), Lacosamide (LCM), and Perampanel (PER). Results: The principal benefit of the newest AEDs, in addition to reduced frequency and seizure severity, is the low number and severity of ADRs reported compared to more historic drugs. Conclusion: Early detection of ADRs could lead to an improvement in patients' quality of life, therefore it is important to monitor ADRs and to adequately perform post marketing surveillance in the clinical practice setting.
... DAT is localized in the axons as well as dendrites and neuronal perikarya of both mesolimbic and nigrostriatal dopaminergic neurons (Nirenberg et al., 1996) and reuptakes extracellular dopamine back into presynaptic neurons, thus playing a key role in shaping dopaminergic neurotransmission (Kahlig and Galli, 2003). It has been reported that synthetic cannabinoid agonists inhibit DAT activity in vitro, in rat striatal synaptosomes (Price et al., 2007;Pandolfo et al., 2011). In the present study, the reduced DAT mRNA and binding levels in SNpc and VTA after chronic and acute WIN55,212-2 administration indicate diminished dopamine uptake by the dendrites of the dopaminergic neurons in SN and VTA. ...
Article
Cannabinoid administration modulates dopamine transmission via an indirect, multisynaptic mechanism that includes the activation of cannabinoid type-1 receptor (CB1R). The present study evaluated in rodents, the effects of acute and chronic (20 days) WIN55,212-2 administration, a non-selective CB1R agonist, on dopamine uptake and synthesis in the mesolimbic and nigrostriatal dopaminergic pathways and associate them to its effects on the endocannabinoid system. The effect of spontaneous withdrawal, after different abstinence periods (7 days, 20 days), was also assessed. Acute and chronic administration of WIN55,212-2 decreased dopamine transporter (DAT) binding and mRNA levels, as well as tyrosine hydroxylase (TH) mRNA expression in the substantia nigra (SN) and ventral tegmental area (VTA). In the striatum, chronic WIN55,212-2 administration led to decreased protein expression of DAT and TH, whereas no alterations were observed after acute administration, suggesting a diminished dopamine uptake and synthesis after chronic agonist treatment. Furthermore, after chronic agonist treatment, we observed reduced CB1R binding and mRNA levels in SN and striatum, providing evidence for a possible regulatory role of the endocannabinoid system on dopaminergic function. Seven days after WIN55,212-2 cessation, we observed a rebound increase in mRNA, binding and total protein levels of DAT and TH in VTA, SN and striatum proposing the existence of a biphasic expression pattern, which was also observed in CB1R binding levels. Within the 20-day period of abstinence, TH mRNA and protein levels and CB1R binding levels remain increased. The above results indicate that chronic CB1R agonist treatment induces long-lasting control of the mesostriatal dopaminergic activity.
... The blockade of sodium channels by CBD may not directly correlate with anticonvulsant effects [106] but may involve activation and desensitization of transient receptor potential vanilloid 1 (TRPV1) channels to reduce hyperexcitability [107]. Alternative mechanisms of CBD action include its ability to hinder the uptake of adenosine, an endogenous anticonvulsant [108,109], and inhibit the uptake and degradation of anandamide, an endocannabinoid [92,110]. ...
Article
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The hippocampus is one of the most susceptible regions in the brain to be distraught with status epilepticus (SE) induced injury. SE can occur from numerous causes and is more frequent in children and the elderly population. Administration of a combination of antiepileptic drugs can abolish acute seizures in most instances of SE but cannot prevent the morbidity typically seen in survivors of SE such as cognitive and mood impairments and spontaneous recurrent seizures. This is primarily due to the inefficiency of antiepileptic drugs to modify the evolution of SE-induced initial precipitating injury into a series of epileptogenic changes followed by a state of chronic epilepsy. Chronic epilepsy is typified by spontaneous recurrent seizures, cognitive dysfunction, and depression, which are associated with persistent inflammation, significantly waned neurogenesis, and abnormal synaptic reorganization. Thus, alternative approaches that are efficient not only for curtailing SE-induced initial brain injury, neuroinflammation, aberrant neurogenesis, and abnormal synaptic reorganization but also for thwarting or restraining the progression of SE into a chronic epileptic state are needed. In this review, we confer the promise of cannabidiol, an active ingredient of Cannabis sativa, for preventing or easing SE-induced neurodegeneration, neuroinflammation, cognitive and mood impairments, and the spontaneous recurrent seizures.
... Evidence for the participation of A 2A R in CBDmediated effects derives from several studies reporting that A 2A R antagonists block the beneficial effects of CBD in animal models of inflammation [11][12][13][14][15]. It has been proposed that this A 2A R-dependent activity of CBD is a product of the ability of CBD to bind itself to the equilibrative nucleoside transporter, thereby inhibiting adenosine uptake, resulting in an indirect activation of A 2A R [16,17]. It could also depend on the previously demonstrated reciprocal antagonistic functional interaction between A 2A R and CB 1 R [18,19], which may be explained, at least in part, by the existence of A 2A R-CB 1 R heteromers [20][21][22]. ...
Article
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At present, clinical interest in the plant-derived cannabinoid compound cannabidiol (CBD) is rising exponentially, since it displays multiple therapeutic properties. In addition, CBD can counteract the undesirable effects of the psychoactive cannabinoid Δ⁹-tetrahydrocannabinol (Δ⁹-THC) that hinder clinical development of cannabis-based therapies. Despite this attention, the mechanisms of CBD action and its interaction with Δ⁹-THC are still not completely elucidated. Here, by combining in vivo and complementary molecular techniques, we demonstrate for the first time that CBD blunts the Δ⁹-THC-induced cognitive impairment in an adenosine A2A receptor (A2AR)-dependent manner. Furthermore, we reveal the existence of A2AR and cannabinoid CB1 receptor (CB1R) heteromers at the presynaptic level in CA1 neurons in the hippocampus. Interestingly, our findings support a brain region-dependent A2AR-CB1R functional interplay; indeed, CBD was not capable of modifying motor functions presumably regulated by striatal A2AR/CB1R complexes, nor anxiety responses related to other brain regions. Overall, these data provide new evidence regarding the mechanisms of action of CBD and the nature of A2AR-CB1R interactions in the brain.
... Dysfunctions in dopamine signaling may also underlie THC-induced impulsive behavior in humans (McDonald et al., 2003). Our previous study showed an intriguing interplay between the cannabinoid and the adenosine systems in dorsolateral striatum, various endo-and exogenous cannabinoid ligands inhibit the synaptic uptake of adenosine and dopamine (Pandolfo et al., 2011). Overall, this evidence re-enforces the ability of the adenosine modulation system to control behavioral inhibition, although the precise role of the different receptors in different brain areas still needs to be clarified. ...
Article
Attention deficit and hyperactivity disorder (ADHD) is characterized by impaired levels of hyperactivity, impulsivity and inattention. Adenosine and endocannabinoid systems tightly interact in the modulation of dopamine signaling, involved in the neurobiology of ADHD. In this study, we evaluated the modulating effects of the cannabinoid and adenosine systems in a tolerance to delay of reward task using the most widely used animal model of ADHD. Spontaneous Hypertensive Rats (SHR) and Wistar‐Kyoto (WKY) rats were treated chronically or acutely with caffeine, a non‐selective adenosine receptor antagonist, or acutely with a cannabinoid agonist (WIN55212‐2, WIN) or antagonist (AM251). Subsequently, animals were tested in the tolerance to delay of reward task, in which they had to choose between a small, but immediate, or a large, but delayed, reward. Treatment with WIN decreased while treatment with AM251 increased the choices of the large reward, selectively in SHR rats, indicating a CB1 receptor‐mediated increase of impulsive behavior. An acute pretreatment with caffeine blocked WIN effects. Conversely, a chronic treatment with caffeine increased the impulsive phenotype and potentiated the WIN effects. The results indicate that both cannabinoid and adenosine receptors modulate impulsive behavior in SHR: the antagonism of cannabinoid receptors might be effective in reducing impulsive symptoms present in ADHD; in addition, caffeine showed the opposite effects on impulsive behavior depending on the length of treatment. These observations are of particular importance to consider when therapeutic manipulation of CB1 receptors is applied to ADHD patients who consume coffee. This article is protected by copyright. All rights reserved.
... CBD is not a full ligand for CB1 or CB2 receptors, having low affinity for these targets [16]. CBD modulates other cellular pathways, such as the transient receptor potential subfamily V member 1 (TRPV1) cation channels [18], GPR55 receptor [19], the enzyme fatty acid amide hydrolase (FAAH) [20], serotonin 1A (5-HT1A) receptor [21], peroxisome proliferator-activated receptor (PPAR)-gamma [22], adenosine uptake [23], calcium channels [24], and opioid receptors [25]. ...
Article
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Cannabidiol (CBD) is the second cannabinoid, in order of importance after Δ9-tetrahydrocannabinol (THC), from Cannabis sativa. Unlike THC, CBD does not cause psychotomimetic effects, and although these compounds have the same chemical formula, their pharmacological characteristics are not equivalent. Preclinical studies suggest that CBD has anti-inflammatory, analgesic, anxiolytic, antiemetic, anticonvulsant, and antipsychotic properties and influences the sleep–wake cycle. The evaluation of effects on spontaneous motor activity is crucial in experimental pharmacology, and the careful measurement of laboratory animal movement is an established method to recognize the effects of stimulant and depressant drugs. The potential influence of CBD on locomotor activity has been investigated through numerous in vivo experiments. However, there is no clear picture of the impact of CBD on these issues, even though it is administered alone for medical uses and sold with THC as a drug for pain caused by muscle spasms in multiple sclerosis, and it was recently licensed as a drug for severe forms of infantile epilepsy. On this basis, with the aim of developing deeper knowledge of this issue, scientific data on CBD’s influence on locomotor activity are discussed here. We conducted research using PubMed, Scopus, Google Scholar, and a search engine for literature between January 2009 and December 2021 on life sciences and biomedical topics using the keywords “motor activity”, “locomotor activity”, and “locomotion” in combination with “cannabidiol”. In this article, we discuss findings describing the effects on locomotor activity of the CBD precursor cannabidiolic acid and of CBD alone or in combination with THC, together with the effects of CBD on locomotor modifications induced by diseases and on locomotor changes induced by other substances.
... Furthermore, CBD has been reported to inhibit synaptic uptakes of DA in vitro synaptosome preparations. 92 Clearly, more studies are required to determine whether and how CBD alters the mesolimbic DA system activity. ...
Article
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A growing number of studies suggest therapeutic applications of cannabidiol (CBD), a recently U.S. Food and Drug Administration (FDA)–approved medication for epilepsy, in treatment of many other neuropsychological disorders. However, pharmacological action and the mechanisms by which CBD exerts its effects are not fully understood. Here, we examined the effects of CBD on oral sucrose self‐administration in rodents and explored the receptor mechanisms underlying CBD‐induced behavioral effects using pharmacological and transgenic approaches. Systemic administration of CBD (10, 20, and 40 mg/kg, ip) produced a dose‐dependent reduction in sucrose self‐administration in rats and in wild‐type (WT) and CB1−/− mice but not in CB2−/− mice. CBD appeared to be more efficacious in CB1−/− mice than in WT mice. Similarly, pretreatment with AM251, a CB1R antagonist, potentiated, while AM630, a selective CB2R antagonist, blocked CBD‐induced reduction in sucrose self‐administration, suggesting the involvement of CB1 and CB2 receptors. Furthermore, systemic administration of JWH133, a selective CB2R agonist, also produced a dose‐dependent reduction in sucrose self‐administration in WT and CB1−/− mice, but not in CB2−/− mice. Pretreatment with AM251 enhanced, while AM630 blocked JWH133‐induced reduction in sucrose self‐administration in WT mice, suggesting that CBD inhibits sucrose self‐administration likely by CB1 receptor antagonism and CB2 receptor agonism. Taken together, the present findings suggest that CBD may have therapeutic potential in reducing binge eating and the development of obesity. Cannabidiol is a recently U.S. FDA approved medication for the treatment of epilepsy. In this study, we found that it is also effective in controlling food‐taking behavior in rats and mice largely by activation of cannabinoid CB2 receptor.
... However, the mechanisms responsible for the anticonvulsant effect of CBD remain unclear. Previous experimental studies have reported that the anticonvulsant effect of CBD is linked to the modulating effects on neuronal hyperexcitability through the antagonism of G protein-coupled receptor 55 (GPR55), of which CBD is a negative allosteric modulator (Laprairie et al., 2015), desensitization of TRPV1 (Chen and Hackos, 2015) and inhibition of adenosine reuptake by blocking equilibrative nucleotide transporter 1 (ENT1), which increases the concentration of extracellular adenosine (Pandolfo et al., 2011). These mechanisms decrease intracellular Ca 2+ flux and regulate neuronal hyperexcitability. ...
Article
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Neural hyperexcitability in the event of damage during early life, such as hyperthermia, hypoxia, traumatic brain injury, status epilepticus, or a pre-existing neuroinflammatory condition, can promote the process of epileptogenesis, which is defined as the sequence of events that converts a normal circuit into a hyperexcitable circuit and represents the time that occurs between the damaging event and the development of spontaneous seizure activity or the establishment of epilepsy. Epilepsy is the most common neurological disease in the world, characterized by the presence of seizures recurring without apparent provocation. Cannabidiol (CBD), a phytocannabinoid derived from the subspecies Cannabis sativa (CS), is the most studied active ingredient and is currently studied as a therapeutic strategy: it is an anticonvulsant mainly used in children with catastrophic epileptic syndromes and has also been reported to have anti-inflammatory and antioxidant effects, supporting it as a therapeutic strategy with neuroprotective potential. However, the mechanisms by which CBD exerts these effects are not entirely known, and the few studies on acute and chronic models in immature animals have provided contradictory results. Thus, it is difficult to evaluate the therapeutic profile of CBD, as well as the involvement of the endocannabinoid system in epileptogenesis in the immature brain. Therefore, this review focuses on the collection of scientific data in animal models, as well as information from clinical studies on the effects of cannabinoids on epileptogenesis and their anticonvulsant and adverse effects in early life.
... CBD can also directly stimulate potential vanilloid channel type 1 (TRPV-1) receptors (De Petrocellis et al. 2011) and acts as an indirect agonist of these receptors by enhancing the levels of AEA, an endogenous agonist of TRPV-1 Rimmerman et al. 2011). CBD is an antagonist of the Gcoupled receptors GPR18 (McHugh et al. 2012) and GPR55 (Ryberg et al. 2007) and binds to equilibrative nucleoside transporter (ENT) (Carrier et al. 2006), adenosine receptors (Carrier et al. 2006;Pandolfo et al. 2011), glycine receptors (Ahrens et al. 2009), serotonin 1A receptor (5-HT1A) (Russo et al. 2005), and peroxisome proliferator-activated receptor-γ (PPAR-γ) (O'Sullivan et al. 2009). CBD influences dopaminergic neurotransmission by inhibiting the dopamine uptake transporter (Pandolfo et al. ...
Article
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Parkinson’s disease (PD) and l-DOPA-induced dyskinesia (LID) are motor disorders with significant impact on the patient’s quality of life. Unfortunately, pharmacological treatments that improve these disorders without causing severe side effects are not yet available. Delay in initiating l-DOPA is no longer recommended as LID development is a function of disease duration rather than cumulative l-DOPA exposure. Manipulation of the endocannabinoid system could be a promising therapy to control PD and LID symptoms. In this way, phytocannabinoids and synthetic cannabinoids, such as cannabidiol (CBD), the principal non-psychotomimetic constituent of the Cannabis sativa plant, have received considerable attention in the last decade. In this review, we present clinical and preclinical evidence suggesting CBD and other cannabinoids have therapeutic effects in PD and LID. Here, we discuss CBD pharmacology, as well as its neuroprotective effects and those of other cannabinoids. Finally, we discuss the modulation of several pro- or anti-inflammatory factors as possible mechanisms responsible for the therapeutic/neuroprotective potential of Cannabis-derived/cannabinoid synthetic compounds in motor disorders.
... CBD has been shown to inhibit the equilibrative nucleoside transporter (ENT1) that is involved in the synaptic uptake of adenosine, thereby increasing extracellular adenosine. The increased levels of extracellular adenosine, in turn, decrease neuronal hyperexcitability and neurotransmission [113][114][115]. Another potential route of antiseizure activity for CBD could be its inhibition of voltage-dependent anion selective channel protein (VDAC1) channel conductance, which could have an immunosuppressive effect and, hence, downregulate neuroinflammation [116]. ...
Article
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Epilepsy is a neurological disorder that affects approximately 50 million people worldwide. There is currently no definitive epilepsy cure. However, in recent years, medicinal cannabis has been successfully trialed as an effective treatment for managing epileptic symptoms, but whose mechanisms of action are largely unknown. Lately, there has been a focus on neuroinflammation as an important factor in the pathology of many epileptic disorders. In this literature review, we consider the links that have been identified between epilepsy, neuroinflammation, the endocannabinoid system (ECS), and how cannabinoids may be potent alternatives to more conventional pharmacological therapies. We review the research that demonstrates how the ECS can contribute to neuroinflammation, and could therefore be modulated by cannabinoids to potentially reduce the incidence and severity of seizures. In particular, the cannabinoid cannabidiol has been reported to have anti-convulsant and anti-inflammatory properties, and it shows promise for epilepsy treatment. There are a multitude of signaling pathways that involve endocannabinoids, eicosanoids, and associated receptors by which cannabinoids could potentially exert their therapeutic effects. Further research is needed to better characterize these pathways, and consequently improve the application and regulation of medicinal cannabis.
... CBD interrelates with neurotransmitter systems, which are essential for the effects of opioids and psychostimulants. For instance, CBD can allosterically regulate δ and μ opioid receptors (23) and cannot inhibit uptake in striatal dopamine synapses (24). Previous research revealed a reversed decline in expressing intraaccumbal AMPA glutamate receptor GluA1 subunits in heroin-trained mice after treating with CBD (19). ...
Article
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As a strong and addictive psychostimulant, methamphetamine (METH) is often misused worldwide. Although relapse is the greatest challenge to the effective treatment of drug dependency, now, for METH addiction, there is not available accepted pharmacotherapy. To characterize a probable new target in this indication, a biological system comprised of endocannabinoids, known as the endocannabinoid system (ECS), has been advised. As a non-psychotomimetic Phytocannabinoid in Cannabis sativa, cannabidiol (CBD) has been used in preclinical and clinical studies for treating neuropsychiatric disorders. In this review article, we focus on the effects of CBD in the treatment of addiction in a preclinical investigation concerning the pharmaceutic effectiveness and the underlying mechanisms of action on drug abuse specially METH. Growing evidence shows that CBD is a potential therapeutic agent in reducing drug reward, as evaluated in conditioned place preference (CPP), brain-stimulation reward paradigms, and self- administration. Furthermore, CBD plays an effective role in decreasing relapse in animal research. Through multiple-mechanisms, there is a belief that CBD modulates brain dopamine responding to METH, resulting in a reduction of METH-seeking behaviors. As our studies indicate, CBD can decrease METH addiction-associated problems, for example, symptoms of withdrawal and craving. It is needed for conducting more preclinical investigations and upcoming clinical trials to entirely assess the CBD capability as interference for METH addiction.
... The antiseizure mechanism of action of CBD is unresolved but likely independent of its action on the endocannabinoid system [24,25]. Several antiseizure mechanisms have been hypothesized, with few identified as most relevant [26][27][28][29][30][31]. (Table 2) Specifically for antiseizure action in TSC, facilitation of gamma-aminobutyric acid (GABA)ergic neurotransmission and activation of mTOR intracellular protein pathway may be most suitable for further investigation. ...
Article
Cannabidiol (CBD) has recently been approved as an add-on therapy by various regulatory agencies for tuberous sclerosis complex (TSC)-associated seizures based on its short-term efficacy and safety in a pivotal randomized controlled trial. However, critical information about which patients with TSC and seizure types respond best to CBD (clinical, electrophysiological, and genetic predictors of responsiveness), when to use CBD in the treatment algorithm, and how CBD can be combined with other antiseizure medications (ASMs) in the form of a rational polypharmacy therapy is still lacking. In general, there is a limited in-depth critical review of CBD for the treatment of TSC to facilitate its optimal use in a clinical context. Here, we utilized a scoping review approach to report the current evidence of efficacy and safety of pharmaceutical-grade CBD in patients with TSC, including relevant mechanism of action and drug–drug interactions with other ASMs. We also discussed emerging information about CBD’s long-term efficacy and safety data in patients with TSC. Finally, we discussed some critical unanswered questions in several domains related to effective clinical management of TSC using CBD, including barriers to early and aggressive treatment in infants, difficulty with universal access to CBD, a lack of studies to understand CBD’s impact on seizure severity and specific seizure types, insufficient exploration of CBD in TSC-related cognitive and behavioral issues, and the need for more research into CBD’s effects on various biomarkers.
... An increase in dopamine release is consistent with previous evidence showing an increase of dopamine turnover in DLS of adult rats after repeated treatment with WIN 55212-2 (2 mg/kg) during early adolescence (PD 35-48) (Bortolato et al., 2014). Although an inhibitory effect of acute WIN 55212-2 on dopamine uptake has been observed in adolescent (Pérez-Valenzuela et al., 2019) and adult (Pandolfo et al., 2011) rats, no changes in dopamine Ed in DLS was evident in adult rats, suggesting that adolescent Figure 3. Adolescent exposure to WIN 55212-2 increased dopamine release and dopamine extracellular concentration (C ext ) in DLS in adult rats. In vivo no-net flux microdialysis in anesthetized adult rats was carried out in vehicle (n = 6) and WIN 55212-2 adolescent exposed rats (n = 6). ...
Article
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During adolescence, neuronal circuits exhibit plasticity in response to physiological changes and to adapt to environmental events. Nigrostriatal dopaminergic pathways are in constant flux during development. Evidence suggests a relationship between early use of cannabinoids and psychiatric disorders characterized by altered dopaminergic systems, such as schizophrenia and addiction. However, it remains unclear what is the impact of adolescent exposure to cannabinoids on nigrostriatal dopaminergic pathways in adulthood. The aim of this research is to determine the effects of repeated activation of cannabinoid receptors during adolescence on dopaminergic activity of nigrostriatal pathways and the mechanisms underlying this impact during the adulthood. Male Sprague-Dawley rats were treated with 1.2 mg/kg WIN 55212-2 daily from postnatal day 40 to 65, then no-net flux microdialysis of dopamine in the dorsolateral striatum (DLS), electrophysiological recording of dopaminergic neuronal activity, and microdialysis measures of GABA and glutamate in substantia nigra par compacta (SNc) were carried out during adulthood (Postnatal day 72 – 78). Repeated activation of cannabinoid receptors during adolescence increased the release of dopamine in DLS accompanied by an increase in population activity of dopamine neurons and a decrease of extracellular GABA levels in SNc in adulthood. Furthermore, perfusion of bicuculline, GABAa antagonist, into the ventral pallidum (VP) reversed the increased dopamine neuron population activity in SNc induced by adolescent cannabinoid exposure. These results suggest that adolescent exposure to cannabinoid agonists produces disinhibition of nigrostriatal dopamine transmission during adulthood mediated by a decrease in GABAergic input from the VP.
... In addition, CBD also acts as an antagonist of the orphan receptor coupled to the G 55 protein (GPR55), an allosteric modulator of the opioid mu and delta receptors, an agonist of the transient receptors of the cation channel subfamily V (TRPV1) [26] and an agonist of the activated peroxisome proliferating gamma receptor (PPARγ) [27]. Finally, CBD also exerts modulation of neurotransmission by AEA, since it is an inhibitor of the AEA transporter and the FAAH enzyme [26], and by adenosine, since CBD inhibits the reuptake of this neurotransmitter [28]. Although these are possible mechanisms mediated by CBD, the pharmacology of CBD is complex, due to the other target and to the sites of action in the brain (see reviews: [27,29,30]). ...
Article
Background Major depressive disorder (MDD) affects millions of people worldwide. While the exact pathogenesis is yet to be elucidated, the role of neuro-immune signaling has recently emerged. Despite major advances in pharmacotherapy, antidepressant use is marred by limited efficacy and potential side effects. Cannabidiol (CBD), a phytocannabinoid, exerts antidepressant-like effects in experimental animals. This study investigated the impact of CBD on sickness behavior (SB), a measure of depressive-like response, and neuro-immune changes induced by lipopolysaccharides (LPS) in mice.Methods Socially isolated rodents were administered with LPS to trigger SB. and treated with CBD or its vehicle. Animals were submitted to forced swimming test, to evaluate depressive-like behavior, and to open field test, to evaluate locomotory activity. Immediately after behavioral analyses, animals were euthanized and had their hypothalamus, prefrontal cortex and hippocampus dissected, to proceed neurotrophins and cytokines analyses. ELISA was used to detect IL-1β, BDNF and NGF; and cytometric beads array to measure IL-2, IL-4, IL-6, IFN-γ, TNF-α and IL-10 levels.ResultsCBD effectively prevented SB-induced changes in the forced swim test without altering spontaneous locomotion. This phytocannabinoid also partially reversed LPS-evoked IL-6 increase in both the hypothalamus and hippocampus. In addition, CBD prevented endotoxin-induced increase in BDNF and NGF levels in the hippocampus of SB animals.Conclusions Apparently, CBD prevents both behavioral and neuro-immunological changes associated with LPS-induced SB, which reinforces its potential use as an antidepressant which modulates neuroinflammation. This opens up potentially new therapeutic avenues in MDD.
... Additionally, CBD inhibits the equilibrative nucleoside transporter (ENT1) responsible for the synaptic uptake of adenosine, thereby increasing levels of extracellular adenosine. Consequently, an upregulation in extracellular adenosine can cascade into a decrease in neuronal hyperexcitability (187)(188)(189). CBD has anti-oxidative and anti-inflammatory properties that could counter neuroinflammation; modulation of TRPV1, CB2R, and GPR55 receptors can lead to downregulation of enzymes involved in the production of pro-inflammatory PGs, reactive oxygen species, and cytokines (190,191). ...
Article
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Neurodevelopmental and neuropsychiatric disorders (such as autism spectrum disorder) have broad health implications for children, with no definitive cure for the vast majority of them. However, recently medicinal cannabis has been successfully trialled as a treatment to manage many of the patients' symptoms and improve quality of life. The cannabinoid cannabidiol, in particular, has been reported to be safe and well-tolerated with a plethora of anticonvulsant, anxiolytic and anti-inflammatory properties. Lately, the current consensus is that the endocannabinoid system is a crucial factor in neural development and health; research has found evidence that there are a multitude of signalling pathways involving neurotransmitters and the endocannabinoid system by which cannabinoids could potentially exert their therapeutic effects. A better understanding of the cannabinoids' mechanisms of action should lead to improved treatments for neurodevelopmental disorders.
... In sum, Liou et al. showed that CBD inhibits adenosine reuptake through ENT1, which indirectly causes the enhanced activation of A 2A adenosine receptor and reduction of TNF-α release [44]. The effects of CBD on ENT1 and adenosine receptors are corroborated by reports in rat and mouse striatal terminals [80] and in EOC-20 murine microglial cells [81]. ...
Article
Cannabidiol (CBD), the major non-intoxicating constituent of Cannabis sativa, has gained recent attention due to its putative therapeutic uses for a wide variety of diseases. CBD was discovered in the 1940s and its structure fully characterized in the 1960s. However, for many years most research efforts related to cannabis derived chemicals have focused on D9-tetrahydrocannabinol (THC). In contrast to THC, the lack of intoxicating psychoactivity associated with CBD highlights the potential of this cannabinoid for clinical drug development. This review details in vitro and in vivo studies of CBD related to the eye, the therapeutic potential of cannabidiol for various ocular conditions, and molecular targets and mechanisms for CBD-induced ocular effects. In addition, challenges of CBD applications for clinical ocular therapeutics and future directions are discussed.
... The main mechanism of action of cocaine is the blockade of the DAT function preventing dopamine reuptake and leading to an upregulation after repeated administration [39][40][41][42]. Interestingly, CBD (40 mg/kg) completely normalized DAT gene expression, suggesting an inhibitory action consistent with a previous study that inferred that CBD may act as a low-potency inhibitor of DAT in rat striatal terminals [43]. Considering its crucial role in the actions induced by cocaine, it is possible to hypothesise that this effect may be closely related with the CBD-mediated improvement of cocaine withdrawal behaviours. ...
... CBD was only effective to normalize DAT levels in mice primed with cocaine, a fact that confirms the importance of dopamine in priming-induced reinstatement. In this respect, previous reports suggested that CBD may act as a low potency inhibitor of DAT in rat striatal neurons (Pandolfo et al., 2011). To confirm and further elucidate how CBD modulates DAT function and dopamine re-uptake, performing additional experimental approaches, such as amperimetry or microdialysis studies, could provide relevant information. ...
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Background Cocaine dependence is an important problem without any effective pharmacological treatment. Some preclinical studies have suggested that cannabidiol (CBD), a component of the Cannabis sativa plant, could be useful for the treatment of cocaine use disorders. Aims This work aims to evaluate the ability of CBD to reduce priming- and stress-induced reinstatement of the conditioned place preference (CPP) induced by cocaine. Methods Young adult CD-1 male mice were allocated to 10 groups ( n = 12/group), conditioned with cocaine (10 mg/kg) and exposed to extinction of CPP (two sessions per week). When extinction was achieved, each group received the corresponding treatment before the reinstatement test. In experiment 1, six groups were used: vehicle+saline (Veh+Sal), 5 mg/kg cocaine alone (Veh+Coc) or with CBD 30 or 60 mg/kg (CBD30+Coc, CBD60+Coc) and CBD alone (CBD30+Sal, CBD60+Sal). In experiment 2, four groups were used: exploration (Veh+Expl), social defeat (Veh+SD) and social defeat with CBD (CBD30+SD and CBD60+SD). Furthermore, the relative gene expression of the dopamine transporter (DAT) in the ventral tegmental area was measured. Results All mice acquired cocaine CPP and extinguished it after three or four weeks. Only the groups treated with cocaine priming (Veh+Coc) or exposed to social defeat (Veh+SD) showed reinstatement of CPP. Interestingly, CBD itself did not induce reinstatement and blocked the reinstating effects of cocaine priming and social defeat. Furthermore, cocaine priming increased DAT gene expression in the ventral tegmental area and CBD completely reversed this effect. Conclusion These results suggest that CBD could reduce reinstatement to cocaine seeking after a period of abstinence.
... Additional targets, including key elements of the opioidergic, dopaminergic, glutamatergic and serotonergic systems have been associated with the actions of CBD. CBD inhibits the reuptake of dopamine and glutamate in vitro [75,76]. Besides, CBD is an allosteric modulator of mu and delta opioid receptors [77,78] and a partial agonist of dopamine D 2 receptors, reinforcing its potential as an antipsychotic [79,80]. ...
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The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD displays an interesting pharmacological profile without the potential for becoming a drug of abuse, unlike THC. In this review, we focused on the anxiolytic, antidepressant, and antipsychotic effects of CBD found in animal and human studies. In rodents, results suggest that the effects of CBD depend on the dose, the strain, the administration time course (acute vs. chronic), and the route of administration. In addition, certain key targets have been related with these CBD pharmacological actions, including cannabinoid receptors (CB1r and CB2r), 5-HT1A receptor and neurogenesis factors. Preliminary clinical trials also support the efficacy of CBD as an anxiolytic, antipsychotic, and antidepressant, and more importantly, a positive risk-benefit profile. These promising results support the development of large-scale studies to further evaluate CBD as a potential new drug for the treatment of these psychiatric disorders.
... The main mechanism of action of cocaine is the blockade of the DAT function preventing dopamine reuptake and leading to an upregulation after repeated administration [39][40][41][42]. Interestingly, CBD (40 mg/kg) completely normalized DAT gene expression, suggesting an inhibitory action consistent with a previous study that inferred that CBD may act as a low-potency inhibitor of DAT in rat striatal terminals [43]. Considering its crucial role in the actions induced by cocaine, it is possible to hypothesise that this effect may be closely related with the CBD-mediated improvement of cocaine withdrawal behaviours. ...
Article
The aim of this study was to evaluate the effects of cannabidiol (CBD) on the behavioural and gene expression changes in a new animal model of spontaneous cocaine withdrawal. For this purpose, male CD-1 mice were exposed to progressive increasing doses of cocaine for 12 days (15 to 60 mg/kg/day, i.p.), evaluating spontaneous cocaine withdrawal 6 h after the last cocaine administration. The effects of CBD (10, 20, and 40 mg/kg, i.p.) were evaluated on cocaine withdrawal–induced alterations in motor activity, somatic signs, and anxiety-like behaviour. Furthermore, gene expression changes in dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the ventral tegmental area, and in cannabinoid receptors 1 (CNR1) and 2 (CNR2) in the nucleus accumbens, were analysed by real-time PCR. The results obtained in the study showed that mice exposed to the spontaneous cocaine withdrawal model presented increased motor activity, somatic withdrawal signs, and high anxiety-like behaviour. Interestingly, the administration of CBD normalized motor and somatic signs disturbances and induced an anxiolytic effect. Moreover, the administration of CBD blocked the increase of DAT and TH gene expression in mice exposed to the cocaine withdrawal, regulated the decrease of CNR1 and induced an additional upregulation of CNR2 gene expression. Thus, this model of spontaneous cocaine withdrawal induces clear behavioural and gene expression changes in mice. Interestingly, CBD alleviates these behavioural and gene expression alterations suggesting its potential for the management of cocaine withdrawal.
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The legalization of cannabis in many countries, as well as the decrease in perceived risks of cannabis, have contributed to the increase in cannabis use medicinally and recreationally. Like many drugs of abuse, cannabis and cannabis-derived drugs are prone to misuse, and long-term usage can lead to drug tolerance and the development of Cannabis Use Disorder (CUD). These drugs signal through cannabinoid receptors, which are expressed in brain regions involved in the neural processing of reward, habit formation, and cognition. Despite the widespread use of cannabis and cannabinoids as therapeutic agents, little is known about the neurobiological mechanisms associated with CUD and cannabinoid drug use. In this article, we discuss the advances in research spanning animal models to humans on cannabis and synthetic cannabinoid actions on synaptic transmission, highlighting the neurobiological mechanisms following acute and chronic drug exposure. This article also highlights the need for more research elucidating the neurobiological mechanisms associated with CUD and cannabinoid drug use.
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Objective: CBD is a phytocannabinoid compound derived from the cannabis plant and has been gaining attention as a potential anxiolytic, anti-panic, and analgesic without the psychoactive effects associated with tetrahydrocannabinol; however, these beneficial therapeutic effects have not yet been explored in dogs and cats. Design: We conducted an open-label study in eight dogs and four cats with each diagnostic symptom and investigated the efficacy, tolerability, and safety of CBD products for treatment. The efficacy of CBD in dogs and cats with problematic behaviors, such as conflict-related, fear-related, repetitive or self-injury behaviors, were assessed. Methods: CBD at 0.15–1.85 mg/kg/day was administered twice daily on an empty stomach with a small piece of food. Behavioral symptoms were measured before the first application (day 0) and after 2 (day 14), 4 (day 28), or 8 weeks (day 56) of regular administration. The efficacy was assessed using a behavior index and rating the degree of overall owner satisfaction and veterinarian observational results. Result: At the end of the study, among the twelve animals that continued to receive this supplement for 8 weeks, four cases were rated as considerably decreased and six were rated as decreased. Conclusion: CBD was used at a dose of 0.3–1.7 mg/kg/day in 8 dogs and 4 cats for 8 weeks, then behavioral changes were observed in 10 subjects. No serious adverse events were observed, and there were no notable problems in safety and tolerability.
Article
Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one Δ(9)-tetrahydrocannabinol, and 2) the adaptive pro-homeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.
Article
The Cannabis sativa plant has been used to treat various physiological and psychiatric conditions for millennia. Current research is focused on isolating potentially therapeutic chemical constituents from the plant for use in the treatment of many central nervous system disorders. Of particular interest is the primary nonpsychoactive constituent cannabidiol (CBD). Unlike Δ9-tetrahydrocannabinol (THC), CBD does not act through the cannabinoid type 1 (CB1) receptor but has many other receptor targets that may play a role in psychiatric disorders. Here we review preclinical and clinical data outlining the therapeutic efficacy of CBD for the treatment of motivational disorders such as drug addiction, anxiety, and depression. Across studies, findings suggest promising treatment effects and potentially overlapping mechanisms of action for CBD in these disorders and indicate the need for further systematic investigation of the viability of CBD as a psychiatric pharmacotherapy. Expected final online publication date for the Annual Review of Neuroscience Volume 39 is July 08, 2016. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
Article
Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal. In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS. Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex. The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances. About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.
Chapter
The objectives of the present chapter are to review and describe the studies made on cannabidiol (CBD), a nonpsychotomimetic constituent of the Cannabis sativa plant, as an anxiolytic compound, and to discuss its possible mechanisms of action. The papers selected for the chapter were identified through systematic searches in the main electronic databases, and the reference lists of the included articles, review publications, and book chapters were hand-searched for additional references. We included both experimental laboratory animal and human studies. Taken together, the studies assessed in the present chapter clearly suggest an anxiolytic-like effect of CBD, both in animal models and in healthy volunteers. In addition, this cannabinoid was shown to decrease anxiety in patients with social phobia. Novel clinical trials involving patients with other anxiety disorders, such as panic, obsessive-compulsive, social anxiety, and posttraumatic stress disorders are now necessary and opportune. However, the optimal therapeutic window of CBD and the mechanisms involved in its anxiolytic action remain to be determined.
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Cannabis sativa has been used for recreational, therapeutic and other uses for thousands of years. The plant contains more than 120 C21 terpenophenolic constituents named phytocannabinoids. The Δ9-tetrahydrocannabinol type class of phytocannabinoids comprises the largest proportion of the phytocannabinoid content. Δ9-tetrahydrocannabinol was first discovered in 1971. This led to the discovery of the endocannabinoid system in mammals, including the cannabinoid receptors CB1 and CB2. Δ9-Tetrahydrocannabinol exerts its well-known psychotropic effects through the CB1 receptor but this effect of Δ9-tetrahydrocannabinol has limited the use of cannabis medicinally, despite the therapeutic benefits of this phytocannabinoid. This has driven research into other targets outside the endocannabinoid system and has also driven research into the other non-psychotropic phytocannabinoids present in cannabis. This chapter presents an overview of the molecular pharmacology of the seven most thoroughly investigated phytocannabinoids, namely Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabivarin, cannabinol, cannabidiol, cannabidivarin, cannabigerol, and cannabichromene. The targets of these phytocannabinoids are defined both within the endocannabinoid system and beyond. The pharmacological effect of each individual phytocannabinoid is important in the overall therapeutic and recreational effect of cannabis and slight structural differences can elicit diverse and competing physiological effects. The proportion of each phytocannabinoid can be influenced by various factors such as growing conditions and extraction methods. It is therefore important to investigate the pharmacology of these seven phytocannabinoids further, and characterise the large number of other phytocannabinoids in order to better understand their contributions to the therapeutic and recreational effects claimed for the whole cannabis plant and its extracts.
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Acupuncture and its modified forms have been used to treat multiple medical conditions, but whether the diverse effects of acupuncture are intrinsically linked at the cellular and molecular level and how they might be connected have yet to be determined. Recently, an emerging role for the endocannabinoid system (ECS) in the regulation of a variety of physiological/pathological conditions has been identified. Overlap between the biological and therapeutic effects induced by ECS activation and acupuncture has facilitated investigations into the participation of ECS in the acupuncture-induced beneficial effects, which have shed light on the idea that the ECS may be a primary mediator and regulatory factor of acupuncture’s beneficial effects. This review seeks to provide a comprehensive summary of the existing literature concerning the role of endocannabinoid signaling in the various effects of acupuncture, and suggests a novel notion that acupuncture may restore homeostasis under different pathological conditions by regulating similar networks of signaling pathways, resulting in the activation of different reaction cascades in specific tissues in response to pathological insults.
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Rationale Cocaine addiction is a global health problem with no approved pharmacotherapies. Preclinical research indicates the non-intoxicating phytocannabinoid, cannabidiol (CBD), can reduce addiction-relevant behaviour for several drug classes (e.g. ethanol, opiates, psychostimulants) in rodents. However, research into the effects of CBD on cocaine addiction-like behaviours is limited, and the acute effects of CBD on cocaine reward are unknown. Objectives The present experiments sought to clarify the effects of CBD (10 mg/kg) on the acquisition, consolidation, reconsolidation, extinction and drug-primed reinstatement of cocaine (15 mg/kg) conditioned place preference (CPP) in adult male C57BL6/J mice. Methods In five separate experiments, CBD was administered 1) prior to cocaine-context pairings, to target acquisition of cocaine-context memory; 2) immediately after cocaine-context pairings, to target consolidation of cocaine-context memory; 3) after a brief reactivation session, to target reconsolidation of cocaine memory; 4) prior to extinction sessions; and 5) prior to cocaine-primed reinstatement. Results CBD treatment reduced preference for the cocaine-context 20 days after CBD cessation. CBD also reduced consolidation of cocaine memory, and this was evident 1 day after cessation of CBD treatment. Interestingly, CBD treatment also modified cocaine-induced locomotion. CBD did not affect reconsolidation of cocaine-induced place preference, the rate of extinction of cocaine memory, or drug-primed reinstatement of cocaine CPP. Conclusions These findings indicate specific effects of acute 10 mg/kg CBD on cocaine memory processes, suggesting delayed effects on cocaine preference and consolidation of cocaine memory, and support the therapeutic utility of CBD for targeting some drug-associated memory processes.
Article
Background and purpose: It has been suggested that the non-euphorogenic phytocannabinoid cannabidiol (CBD) can ameliorate adverse effects of delta-9-tetrahydrocannabinol (THC). We determined whether CBD ameliorates cognitive deficits and withdrawal signs induced by cannabinoid CB1/CB2 receptor agonists or produces these pharmacological effects on its own. Experimental approach: The effects of THC or the CB1/CB2 receptor full agonist WIN55212 (WIN) alone, CBD alone, or their combination were tested across a range of doses. Cognitive effects were assessed in C57BL/6 mice in a conditional discrimination task and in the Barnes maze. Cannabinoid withdrawal signs were assessed following precipitated withdrawal by acute administration of the CB1 antagonist SR141716, the 5-HT1A receptor antagonist WAY100635, the TRPV1 receptor antagonist capsazepine, or the adenosine A2A receptor antagonist SCH58261. Key results: THC produced significant motor and cognitive impairment in the Barnes maze task, and none of these deficits were attenuated by the addition of CBD. CBD alone did not impact cognitive performance. Precipitation of withdrawal signs by SR141716 occurred in mice chronically treated with THC or WIN, and these withdrawal signs were not attenuated by addition of chronic CBD. Chronic treatment with CBD alone did not induce withdrawal signs precipitated by SR141716 or WAY100635. Chronic CBD treatment also produced anxiolysis and this was not altered by attempting to precipitate withdrawal-induced anxiety with a range of antagonists. Conclusions and implications: These data suggest that CBD as a monotherapy may prove to be a safer pharmacological agent for the treatment of several disorders as compared with CB1 agonism alone or in combination with CBD.
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Cannabis is the most used illicit drug worldwide and its medicinal use is under discussion, being regulated in several countries. However, the psychotropic effects of Δ⁹-tetrahydrocannabinol (THC), the main psychoactive compound of Cannabis sativa, are of concern. Thus, the interest in the isolated constituents without psychotropic activity, such as cannabidiol (CBD) and cannabidivarin (CBDV) is growing. CBD and CBDV are lipophilic molecules with poor oral bioavailability and are mainly metabolized by cytochrome P450 (CYP450) enzymes. The pharmacodynamics of CBD is the best explored, being able to interact with diverse molecular targets, like cannabinoid receptors, G protein-coupled receptor-55, transient receptor potential vanilloid 1 channel and peroxisome proliferator-activated receptor-γ. Considering the therapeutic potential, several clinical trials are underway to study the efficacy of CBD and CBDV in different pathologies, such as neurodegenerative diseases, epilepsy, autism spectrum disorders and pain conditions. The anti-cancer properties of CBD have also been demonstrated by several pre-clinical studies in different types of tumour cells. Although less studied, CBDV, a structural analogue of CBD, is receiving attention in the last years. CBDV exhibits anticonvulsant properties and, currently, clinical trials are underway for the treatment of autism spectrum disorders. Despite the benefits of these phytocannabinoids, it is important to highlight their potential interference with relevant physiologic mechanisms. In fact, CBD interactions with CYP450 enzymes and with drug efflux transporters may have serious consequences when co-administered with other drugs. This review summarizes the therapeutic advances of CBD and CBDV and explores some aspects of their pharmacokinetics, pharmacodynamics and possible interactions. Moreover, it also highlights the therapeutic potential of CBD and CBDV in several medical conditions and clinical applications.
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Toll-like receptors (TLRs) are sensors of pathogen-associated molecules that trigger inflammatory signalling in innate immune cells including macrophages. All TLRs, with the exception of TLR3, promote intracellular signalling via recruitment of the myeloid differentiation factor 88 (MyD88) adaptor, while TLR3 signals via Toll-Interleukin-1 Receptor (TIR)-domain-containing adaptor-inducing interferon (IFN)-β (TRIF) adaptor to induce MyD88-independent signalling. Furthermore, TLR4 can activate both MyD88-dependent and –independent signalling (via TRIF). The study aim was to decipher the impact of the highly purified plant-derived (phyto) cannabinoids Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), when delivered in isolation and in combination (1:1), on MyD88-dependent and -independent signalling in macrophages. We employed the use of the viral dsRNA mimetic poly(I:C) and endotoxin lipopolysaccharide (LPS), to induce viral TLR3 and bacterial TLR4 signalling in human Tamm-Horsfall protein-1 (THP-1)-derived macrophages, respectively. TLR3/TLR4 stimulation promoted the activation of interferon (IFN) regulatory factor 3 (IRF3) and TLR4 promoted the activation of nuclear factor (NF)-κB signalling, with downstream production of the type I IFN-β, the chemokines CXCL10 and CXCL8, and cytokine TNF-α. THC and CBD (both at 10 μM) attenuated TLR3/4-induced IRF3 activation and induction of CXCL10/IFN-β, while both phytocannabinoids failed to impact TLR4-induced IκB-α degradation and TNF-α/CXCL8 expression. The role of CB1, CB2 and PPARγ receptors in mediating the effect of THC and CBD on MyD88-independent signalling was investigated. TLRs are attractive therapeutic targets given their role in inflammation and initiation of adaptive immunity, and data herein indicate that both CBD and THC preferentially modulate TLR3 and TLR4 signalling via MyD88-independent mechanisms in macrophages. This offers mechanistic insight into the role of phytocannabinoids in modulating cellular inflammation.
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Adenosine is an endogenous purine nucleoside and it is extensively present in the brain. It exerts several metabolic and neuromodulatory roles in the body. Adenosine also acts as an important messenger molecule for extracellular signaling and shows a homeostatic neuromodulatory function at the synaptic level. Extracellular adenosine exerts a wide variety of biological actions through four cell surface G-protein-coupled receptor subtypes, namely A 1, A 2A, A 2B and A 3 adenosine receptors. The extracellular levels of adenosine have been found to be enhanced in several neuropathological conditions, including drug addiction, and thus a neuroprotective role of adenosine was perceived by various experimental studies. The aversive withdrawal symptoms emanating from drug discontinuation provokes rebound drug intake patterns. In addition, alteration of neurotransmitter(s) release and changes in receptor expression contribute to the behavioral changes of drug withdrawal. Furthermore, the abuse of major drugs such as alcohol and opioids are reported to modulate extracellular adenosine levels. In this context, the neuromodulatory functions of adenosine would be valuable if projected to the clinical applications and thus, an increasing attention is currently given to the functional role of adenosine in human addictive disorders. This review will focus on recent clinical and experimental studies that reveal the actions of adenosine and related ligands in drug addiction and various drug-withdrawal syndromes. The evidence and reports provided in this review highlight the looming therapeutic potential of purinergic drugs, with a hope that new therapeutic interventions based on the adenosinergic concept will emerge in the coming years for the management of drug withdrawal syndrome.
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The influence of cannabis on mental health receives growing scientific and political attention. An increasing demand for treatment of cannabis dependence has refueled the discussion about the addictive potential of cannabis. A key feature of all addictive drugs is the ability to increase synaptic dopamine levels in the striatum, a mechanism involved in their rewarding and motivating effects. However, it is currently unknown if cannabis can stimulate striatal dopamine neurotransmission in humans. Here we show that Δ9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, induces dopamine release in the human striatum. Using the dopamine D2/D3 receptor tracer [11C]raclopride and positron emission tomography in seven healthy subjects, we demonstrate that THC inhalation reduces [11C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions. These results suggest that THC shares a potentially addictive property with other drugs of abuse. Further, it implies that the endogenous cannabinoid system is involved in regulating striatal dopamine release. This allows new directions in research on the effects of THC in neuropsychiatric disorders, such as schizophrenia.
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The function of the central cannabinoid receptor (CB1) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of the CB1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggest that the CB1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior.
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The previous chapters provided us with detailed reviews on the molecular biology and pharmacology of major endocannabinoid and endovanilloid ligands (namely, anandamide and 2-arachidonoylglycerol) and their receptors (CB1, CB2 and TRPV1 receptors), which altogether can be termed as “canonical knowledge”. Still, experimental findings often display mismatches with this canonical knowledge: in the last decade, a rapidly increasing number of studies have reported “non-canonical”, “unusual” pharmacological profiles for certain cannabinoid ligands and receptors. Furthermore, from time to time results are explained by suggesting the involvement of a “new receptor”. The present chapter attempts to give a helpful guideline about how to evaluate “non-canonical” results in the cannabinoid field. All the major topics of “non-canonical” cannabinoid pharmacology, namely interactions of endogenous and exogenous cannabinoid and vanilloid ligands with (1) CB1 receptor splice variants, (2) CB1 receptor heterodimers and other non-ionotropic receptors, (3) ligand- and voltagegated ion channels and finally, (4) neurotransmitter uptake systems are thoroughly reviewed. For sake of simplicity, studies reporting unknown cannabinoid receptors without sufficient investigation of other already defined targets are not discussed here. Finally, this review highlights that the “unorthodox sites of action” may be an unavoidable consequence of evolution, providing novel ideas and pharmaceutical targets to modulate signaling systems in neuropsychiatric disorders.
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Converging lines of evidence point to an inextricable role of the endocannabinoid system in schizophrenia. Marijuana consumption (1) elicits psychotic symptoms similar to schizophrenia; (2) precipitates schizophrenia in susceptible individuals; (3) worsens psychosis; and (4) is more prevalent among schizophrenia patients. (5) Genetic linkage studies have mapped a locus around the CB1 cannabinoid receptor gene (CNR1), which potentially confers susceptibility to schizophrenia, and (6) within CNR1, several polymorphisms reportedly associate with this disease. (7) The endocannabinoid system controls brain areas and signalling systems implicated in schizophrenia, (8) and is overactive in patients, (9). It correlates with symptom severity and is reversible with certain antipsychotics. Finally, (10) the naturally occurring CB1 receptor antagonist cannabidiol exhibits a promising antipsychotic profile in pharmacological model-psychoses and schizophrenia. In summarizing the pertinent epidemiological and molecular data, we define schizophrenia as a manifestation of aberrant circuitry formation at the synaptic level and propose that the liability to develop psychosis is driven by imbalanced co-signalling between endocannabinoids and other neuromodulatory pathways already implicated in schizophrenia.
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Multiple lines of evidence indicate a prominent role for the cannabinoid signaling system in the control of basal ganglia function, exerted by modulating the activity of various classic neurotransmitters, such as GABA, dopamine, or glutamate, that operate within this circuit. Throughout the basal ganglia, the activity-evoked release of endocannabinoids has been found to directly regulate the release and plasticity of both excitatory and inhibitory synapses. These observations, together with the demonstration that different elements (receptors, ligands, enzymes) of the cannabinoid signaling system are markedly disturbed in basal ganglia disorders, namely Parkinson's and Huntington's disease, provide support to the idea that cannabinoidbased medicines, with selectivity for different targets of the cannabinoid signaling system, might have therapeutic benefits in these disorders. These benefits would include the alleviation of specific motor symptoms but they could be also extended to a possible delay or arrest of disease progression based on the neuroprotective and/or neuroregenerative properties of certain cannabinoid compounds. In this chapter we review the anatomical, neurochemical, electrophysiological, and pharmacological bases that sustain the importance of the cannabinoid system in basal ganglia function, attempting also to present current information and future lines for research on the therapeutic potential of this system in basal ganglia disorders.
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Cannabidiol (CBD), a nonpsychotropic, nontoxic compound has been shown to block diabetes- and endotoxin-induced retinal damage. However, the protective mechanism of this anti-inflammatory cannabinoid is not completely understood. The goal of this study is to determine the role of adenosine signaling in retinal inflammation and its potential modulation by CBD. The adenosine receptor (AR) subtypes expressed in rat retinal microglial cells were assessed by quantitative real-time RT-PCR. AR function was determined via in vitro and in vivo inflammatory models. Microglial cells or rats were treated with or without lipopolysaccharide (LPS) in the presence or absence of adenosine, adenosine receptor agonists/antagonists, or CBD. Adenosine uptake and tumor necrosis factor (TNF)-alpha release in cells or in retinas were determined. The results showed that A(2A)ARs are abundantly expressed in rat retinal microglial cells. When the cells or rats were treated with LPS, activation of the A(2A)AR was the most efficient in mediating AR agonist- or CBD-induced TNF-alpha inhibition. CBD inhibited adenosine uptake via equilibrative nucleoside transporter 1 and synergistically enhanced adenosine's TNF-alpha suppression after treatment with LPS. These results suggest that the activated A(2A)AR in the retinal microglial cells plays a major anti-inflammatory role in the retina and that CBD's anti-inflammatory effects are linked to the inhibition of adenosine uptake.
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It is widely accepted that non-endogenous compounds that target CB(1) and/or CB(2) receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with Delta(9)-tetrahydrocannabinol or nabilone, both CB(1)/CB(2) receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB(2)-selective agonists, peripherally restricted CB(1)/CB(2) receptor agonists and CB(1)/CB(2) antagonists and inverse agonists as medicines. Already, numerous cannabinoid receptor ligands have been developed and their interactions with CB(1) and CB(2) receptors well characterized. This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB(1), non- CB(2) G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner. It begins with a brief description of how each of these ligands interacts with CB(1) and/or CB(2) receptors.
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Adenosine A(2A) receptor antagonists are psychomotor stimulants that also hold therapeutic promise for movement disorders. However, the molecular mechanisms underlying their stimulant properties are not well understood. Here, we show that the robust increase in locomotor activity induced by an A(2A) antagonist in vivo is greatly attenuated by antagonizing cannabinoid CB(1) receptor signaling or by administration to CB(1)(-/-) mice. To determine the locus of increased endocannabinoid signaling, we measured the amount of anandamide [AEA (N-arachidonoylethanolamine)] and 2-arachidonoylglycerol (2-AG) in brain tissue from striatum and cortex. We find that 2-AG is selectively increased in striatum after acute blockade of A(2A) receptors, which are highly expressed by striatal indirect-pathway medium spiny neurons (MSNs). Using targeted whole-cell recordings from direct- and indirect-pathway MSNs, we demonstrate that A(2A) receptor antagonists potentiate 2-AG release and induction of long-term depression at indirect-pathway MSNs, but not direct-pathway MSNs. Together, these data outline a molecular mechanism by which A(2A) antagonists reduce excitatory synaptic drive on the indirect pathway through CB(1) receptor signaling, thus leading to increased psychomotor activation.
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