New Insights And Potential Therapeutic Targeting Of CB2 Cannabinoid Receptors in CNS Disorders Part 3

4.1.5. CB2R-ECS in Autism Spectrum Disorder (ASD)

With the recent advances in cannabis and cannabinoid research, along with the increased acceptance of cannabis medicine, cannabinoids have been approved in childhood disorders including epilepsy, as discussed below, and in Autism spectrum disorder (ASD). 

Epilepsy is a serious neurological disease. During the entire course of the disease, patients will not only suffer physical and psychological effects but also cause serious harm to memory. However, we should look at this issue positively and optimistically.

First, we need to understand what epilepsy is. Simply put, epilepsy is abnormal electrical activity in the brain caused by neurons in the brain losing their normal frequency. This can lead to a range of symptoms such as loss of consciousness, convulsions, visual disturbances, etc. The occurrence of epilepsy often affects patients' lives and work, which has a great impact on their memory. However, we should realize that this is only a temporary effect of epilepsy on brain function, and it does not mean that epilepsy will cause permanent memory loss.

Secondly, we must note that memory problems in epilepsy patients can be alleviated. In fact, some medications and other treatments can help control symptoms, thereby helping patients preserve their memory. In addition, epilepsy patients can also use various methods to exercise their brains and improve their memory. For example, learn new things, play reading, spelling, and memory games, and more. The stimulation of the brain by these activities can promote synaptic connections, thereby enhancing memory function.

Finally, we must help people with epilepsy face life positively and optimistically. While epilepsy may have some impact on their memory, it is not a problem they cannot overcome. Many people with epilepsy continue to live successful lives, with excellent jobs and relationships. We should encourage them and let them know that they can achieve their dreams.

To sum up, there is a relationship between epilepsy and memory, but this does not mean that epilepsy will make you lose your memory. Instead, we should actively work to alleviate the symptoms and enhance the memory skills of epilepsy patients, thereby helping them to escape the impact of the disease and live an active, healthy, and successful life. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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ASD has an early childhood onset and a lifelong progression. It is characterized by poor social skills, deficits in communication, as well as stereotypic behaviors [111]. The ECS plays a significant role in ASD. A review of the role of the ECS in autism found that endocannabinoid signaling plays a key role in many human health and disease conditions of the CNS [112]. 

However, there is limited literature, pre-clinical and clinical, on the role of CB2Rs in ASD. CB2Rs were also identified as a possible target for autism in preliminary research. Indeed, in our earlier studies, in the cerebellum of BTBR T + tF/J, a mouse model of ASD, we reported an increased level of CB2A mRNA expression, but not of the CB2BR, gene-transcript isoforms [15]. 

A controlled study of ASD conducted on autistic children showed that gene expression for CNR2 but not CNR1 was up-regulated in peripheral blood mononuclear cells (PBMCs). The result indicated that CNR2 gene expression was significantly higher in individuals with ASD compared to controls. In addition, the gene expression for one of the enzymes responsible for the synthesis of the endocannabinoid anandamide (NAPE-PLD) was significantly lower in individuals with ASD. 

This could have caused an increase in CB2Rs resulting from a decrease in AEA synthesis, which may be indicative of a decreased ECS tone in ASD [113]. While there is a multifactorial and putative link between ECS to ASDs, there are no solid biomarkers. Others are increasingly convinced that a medical cannabis treatment may yield cannabis-responsive biomarkers and that ECS may be altered in ASDs. However, our investigations using BTBR T + tF/J and other preclinical mouse models rely on the characterization of behavioral alterations [15]. 

There is a dearth of basic and clinical research, although our previous studies may support the development of cannabinoids targeting the ECS components. There is support for such a view, as the ECS components provide CB2R neuro-immunomodulatory targets for ASDs [114]. 

It is important that more basic and clinical research be conducted, and trials may unravel the etiology of ASDs, which involve not only multigenetic risk factors but also environmental neurodevelopment factors in utero. With the increasing knowledge on the alteration of the ECS in ASDs, the initial relief of ASD symptoms requires trials to ascertain the use of cannabis and cannabinoids modulating the ECS in ASDs.

4.1.6. CB2R-ECS in Eating Disorders

It is well known that the ECS modulates appetite-a basis for adjunctive cannabinoids use to counter AIDs cachexia-and regulates the metabolism of glucose in the pancreas and liver. "Diabesity" refers to the relationship between diabetes and obesity. 

Even though the leading cause of this metabolic disorder is a poor lifestyle, diabesity is in part linked with ECS signaling in adiposity and metabolism. This indicates that the dysregulation of the gut ECS and altered levels of PCBs are associated with obesity and metabolic syndrome. The physiological roles of the ECS in the gastrointestinal tract (GIT), adipogenesis, and lipogenesis provide an increasing link in the dysfunction of the ECS with obesity, metabolic syndrome, and other disturbances in the periphery. 

The most common eating disorders are anorexia nervosa (AN) and bulimia nervosa (BN), presenting abnormal eating behaviors that generally result in severe food restriction with episodes of binge eating and vomiting, without significant changes of body weight in BN and a dramatic loss of body weight in AN [111]. 

The hypothalamic eCBs have been shown to modulate eating behavior in animals and humans, thus indicating the role of the ECS in the pathophysiology of eating disorders [115,116]. In a study conducted on 20 women with AN, 23 women with BN, and 26 healthy women, the levels of CB1R and CB2R expression were examined. The study found no differences in CB2R mRNA levels in the blood of AN and BN patients when compared to controls, with no significant difference between the two groups [117,118]. 

So far, there is only one study on human genetic association to identify whether the CNR2 gene is involved in eating disorders [119]. A total of 204 individuals with eating disorders (94 AN and 111 BN) and 1876 healthy Japanese volunteers participated in the study. 

A nonsynonymous CNR2 polymorphism was found to be linked to both AN and BN. The R allele is substantially more prevalent in people with eating disorders than in controls, according to the findings. Furthermore, there was no change in allele frequency between patients with AN and BN when they were separated. The studies demonstrate a link between CB2Rs and eating disorders when taken together, but more research is needed to corroborate these findings.

4.2. Potential Role of CB2Rs in Neurologic and Neurodegenerative Disorders

4.2.1. CB2R-ECS in Alzheimer's Disease (AD)

Because of the neuroprotective role of CB2Rs in CNS disorders with neuroinflammatory biomarkers, there has been interest and focus on the potential of targeting CB2Rs in Alzheimer's disease (AD) in several animal models of AD. AD is characterized by the abnormal accumulation of β-amyloid (Aβ) in senile plaques in the brain, which causes cognitive impairment, memory loss, and behavioral changes due to neurodegeneration and inflammation [120]. 

Studies demonstrate that the ECBs have been shown to decrease Aβ-induced microglia activation and neuroinflammation [121–123]. Recently, CB2Rs have attracted attention in AD investigation because of their expression in immune cells and their enhanced expression during inflammation. Studies showed that there is increased expression of CB2Rs in brain tissue in AD patients and mouse models expressing pathogenic variants of the amyloid precursor protein (APP) [121,124,125]. 

Previous research found that the genetic deletion of CB2Rs increased Iba1 staining and exacerbated soluble A42 and plaque deposition [126], implying that CB2Rs play a key role in preventing amyloid plaque pathology in AD [127]. In mice, the administration of JWH-133 improved cognitive impairment, inhibited neuroinflammation and oxidative stress, decreased tau hyperphosphorylation, induced vasodilation [128,129], and enhanced glucose uptake, indicating that CB2R agonists could be used as nootropics [130]. 

A recent study assessing the role of AEA analog-N-linoleyltyrosine (NITyr) in APP/PS1 mice mimicking the AD model showed that NITyr protected neurons against Aβ injury, which is mainly mediated by the CB2Rs [131]. Interestingly Rivas-Santisteban et al. [132] demonstrated that CB2R activation blunted NMDA receptor-mediated signaling in primary hippocampal neurons from an APPSw/Ind mice model of AD, suggesting a role of CB2Rs in AD pathogenesis. In addition, in AD model mice, CB2R activation by JWH-015 was found to improve new object recognition abilities while also regulating microglia-mediated neuroinflammation and dendritic complexity in a region-specific manner (Li et al., 2019) [133]. 

A parenteral administration of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine (MDA7), a novel selective CB2R agonist, inhibited the activation of microglial cells and astrocytes, decreased the level of expression of CB2R, enhanced the clearance of Aβ, and improved cognition and memory in rodent AD models [134,135]. In various in vitro and in vivo AD models, CB2R activation reduced the levels of neurotoxic factors and pro-inflammatory mediators produced by reactive astrocytes and microglial cells, stimulated microglial proliferation and migration, and decreased Aβ levels [136–138]. 

Despite a large body of evidence for the involvement of CB2Rs in reducing and processing Aβ in a mouse model of AD, it is difficult to determine the therapeutic value of cannabis-based medicines in AD [139]. Some reports show that mice with CB2R deficiency showed a reduction in microglial cells and macrophages, reduced expression levels of brain pro-inflammatory cytokines, diminished concentrations of soluble Aβ40/42, and improved cognitive and learning deficits [121]. In a few clinical studies, there are contradictory reports on the potential of the CB2R ligand in AD, and further research is required to determine the potential role of CB2Rs in humans and animal models of AD.

4.2.2. CB2R-ECS in Parkinson's Disease (PD)

Earlier studies indicated changes in the ECS particularly with the interaction of the dopaminergic system and eCBs in basal ganglia associated with movement disturbances, one of the hallmarks of Parkinson's disease (PD). PD is a movement disorder characterized by the degeneration of dopaminergic neurons, that results in motor dysfunction [140,141]. 

Disease progression is characterized by inflammation through the activation of microglia [142] and an increase in cytokines [143,144]. Accumulated evidence suggests that there is a strong potential for the ECS to provide neuroprotection against acute or chronic neurodegenerative disorders [145–149]. CB2R levels were significantly elevated in animal models of PD and postmortem studies of PD patients, and this increase correlated significantly with an increase in microglial activation, indicating the possible role of CB2Rs in PD [61,150]. Studies showed a down-regulation of CB2Rs in the substantia nigra and hippocampus three weeks after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection in mice with MPTP-induced Parkinsonian syndrome. 

In addition, AM1241, the selective CB2R agonist, has been shown to regenerate DA neurons after the neurotoxic effect of MPTP treatment [145]. Furthermore, mice lacking the CB2R showed enhanced activation of microglial cells and a much more intense deterioration of tyrosine hydroxylase (TH)-containing nigral neurons in animal models of PD [150], which supported the potential neuroprotective role of CB2Rs. In animal models of PD, ∆ 9 -THCV, a CB2R agonist, reduced the motor inhibition caused by 6-hydroxydopamine (6-OHDA) and the loss of TH–positive neurons caused by a 6-OHDA lesion in the substantia nigra after acute and chronic administrations, respectively. However, CB2Rs were poorly up-regulated in the rats' substantia nigra in response to 6-OHDA. 

By contrast, the substantia nigra of mice that had been injected with lipopolysaccharide (LPS) exhibited a greater up-regulation of CB2Rs. The authors suggest that ∆ 9 -THCV caused the preservation of TH–positive neurons, probably through the involvement of CB2Rs [151]. In another study, the protective effect of JWH-015 against MPTP-induced nigrostriatal degeneration and the suppression of microglial activation/infiltration through the activation of CB2Rs [152] were implicated. In addition, reports are showing that BCP reduced oxidative stress and neuroinflammation, blocked gliosis and pro-inflammatory cytokine release, and lowered nigrostriatal degeneration in a rotenone (ROT)-induced animal model of PD [153]. 

Like the pre-clinical studies, clinical studies revealed that the expression of CB2Rs in different brain cells is up-regulated in PD patients. One study demonstrated that CB2Rs are elevated in microglial cells recruited and activated at lesioned sites in the substantia nigra of PD patients compared to control subjects [150]. In another study, the authors observed that CB2R was located in TH-containing neurons in the substantia nigra at significantly lower levels in PD patients compared to controls [154]. Thus, CB2Rs may be a promising pharmaceutical target for alleviating Parkinsonian symptoms and slowing disease development in Parkinson's disease.

4.2.3. CB2R-ECS in Huntington's Disease

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of the CAG triplet repeat (cytosine-adenine-guanine) in the gene encoding the protein huntingtin (Htt), which leads to cognitive decline and abnormal motor movements (chorea) [1,155]. Currently, there is no effective treatment for HD, and the need for new therapeutic targets is increasing [1]. Because the ECS is abundant in the basal ganglia, the activation or inhibition of the ECS signaling pathway may have a major impact on motor responses [156], and CB2R is emerging as a new therapeutic target for the treatment and early diagnosis of HD [157]. In the transgenic R6/2, CAG repeat length Huntington chorea mouse model, CB2R expression was shown to be elevated in the hippocampus, brain, striatum, and cerebellum [158]. 

Studies also found that mice lacking CB2Rs were more sensitive to malonate than the control group. In addition, CB2R-deficient mice exhibited an enhanced onset of motor deficits and increased severity [159,160]. The expression of CB2R was increased in striatal microglia in a transgenic mouse model of HD and patients. In addition, the genetic ablation of CB2R exacerbated HD, and the administration of CB2R-selective agonists reduced the striatal neurodegeneration through microglial activation [161]. Taken together, CB2Rs might be a potential target, and compounds that selectively activate CB2R might be utilized as a potential therapeutic agent in the treatment of HD.

4.2.4. CB2R-ECS in Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disorder characterized by the inflammation, neurodegeneration, and demyelination of neurons with no effective therapy [162], and studies showed the role of CB2Rs in inflammatory conditions associated with MS [157,163]. Microglial activation was linked to CB2R overexpression in an experimental autoimmune encephalomyelitis (EAE) animal model of MS [164]. HU-308, the CB2R-selective agonist, also dramatically reduced the EAE symptoms, axonal loss, and microglial activation when administered orally [165]. O-1966, a CB2R agonist, was also found to reduce immune cell invasion, diminish white cell rolling and adhesion to cerebral microvessels, and improve the neurologic function following an insult on the EAE progression [166]. 

Additional research conducted using EAE animal models demonstrated that BCP significantly inhibits microglial cells, CD4+ and CD8+ T lymphocytes, and cytokines, diminishes axonal demyelination and modulates the Th1/Treg immune balance through the activation of CB2Rs [167]. Maresz et al. [164] also reported that the CB2R expression by encephalitogenic T cells reduced the EAE-associated inflammation. Furthermore, during EAE, CB2R-deficient T cells in the CNS showed reduced apoptosis, increased proliferation, and increased production of inflammatory cytokines, resulting in severe clinical illness. The Theiler murine encephalomyelitis virus-induced demyelinating disease (TMEV- IDD), which mimics the central neuronal demyelination that occurs in MS, is another animal model of MS [168]. In TMEV-IDD mice, the CB1R and CB2R agonists showed enhanced clinical benefits through immunomodulatory and anti-inflammatory mechanisms [169,170], which is another evidence for the role of CB2Rs in MS. Postmortem and clinical studies also showed the involvement of CB2Rs in MS. An association between the CB2R rs35761398 (Q63R) polymorphism and MS was found in a study conducted on a total of 100 Iranian MS patients and 100 healthy controls [171]. 

Evidence suggests that MS patients showed a significantly elevated CB2 expression in B cells, but not in T or NK cells [172]. Yiangou et al. [173] indicated a higher level of microglial cells in human postmortem spinal cord specimens. Evidence revealed that T lymphocytes, astrocytes, and both perivascular and reactive microglial cells were also observed to express CB2Rs in postmortem brain tissues from MS donors [174]. These findings suggest that CB2Rs play a neuroprotective function in MS pathology, and targeting CB2Rs could aid in the management of symptoms and neurologic issues in MS patients.

4.2.5. CB2R-ECS in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a degenerative disease affecting the cortex, the brain stem, and the spinal cord motor neurons. The deterioration of both the upper and lower motor neurons is the main feature of disease progression [121,175]. The involvement of CB2Rs in ALS has been demonstrated by different studies. A reduction in motor neuron degeneration and the preservation of the motor function in ALS was observed after selective activation of CB2Rs in animals [176–178]. TDP-43 transgenic mice and postmortem specimen studies showed that there is an up-regulation of CB2Rs in activated microglia cells [173,179]. Studies also showed that the survival interval after ALS onset was increased by 56% after the administration of the CB2R agonist AM1241, initiated at symptom onset [176]. In addition, Kim et al. [177] reported a reduction in the signs of disease progression when AM1241 was administered after the onset of signs in an ALS mouse model (hSOD1(G93A) transgenic mice. Another study done to evaluate the neuroprotective effect of the phytocannabinoid-based medicine Sativex® using SOD1G93A mutant mice, an experimental model of ALS, showed a significant increase of CB2Rs [180]. All this evidence indicates that CB2R plays a role in preventing the progression of ALS. Therefore, CB2Rs might be considered a promising target for therapeutic approaches in ALS.

4.2.6. CB2R-ECS in Epilepsy

Epilepsy is a common neurological illness, affecting more than 70 million individuals worldwide. The currently available anti-epileptic drugs are unable to control epileptic seizures in the majority of patients [181], and hence there is a need for new therapeutic targets for effective anti-epileptic drugs. There is evidence on the role of the ECS in epilepsy [182,183], and studies showed that CBD was effective in the treatment of epileptic seizures in preclinical [184] and clinical studies [185,186]. The role of CB2Rs in epileptic seizures has been documented in other studies [33,187]. A study showed that the selective CB2R antagonist AM630 inhibited a palmitoyl ethanolamide (PEA)-induced increase in the latency of seizure initiation and reduced the duration of seizures in an acute pentylenetetrazol (PTZ) rat seizure model [188]. In addition, the administration of BCP was found to improve seizure activity in a mouse model [189]. Despite the evidence showing the role of CB2Rs in controlling seizures in animals, few studies found a possible association between the activation of CB2Rs and the control of seizures. In a study using a HU-308, a CB2R selective agonist, HU-308 did not show an antiseizure effect, and AM630 did increase seizure severity [190]. Moreover, the CB2R agonist AM1241 increased seizure intensity in a PTZ model [191], and AM630 and SR144528 can increase seizure susceptibility [190]. Studies using genetically manipulated mice revealed that CB2R knockout mice show an enhanced epileptic susceptibility, and a reduction in CB2R activity was associated with increased susceptibility [192]. Taken together, accumulated evidence supports the involvement of CB2Rs in the pathophysiology of epileptic seizures. The enhanced expression of CB2Rs in the brain during various disease states including epilepsy makes them an important target for neuroprotection, and hence CB2Rs might serve as a possible target for the treatment of epilepsy.

4.2.7. CB2R-ECS in Traumatic Brain Injury

Traumatic brain injury (TBI) is caused by a mechanical injury of the brain that results in the formation of a hematoma that ultimately leads to long-term complications and death [193]. Evidence show the involvement of CB2Rs in modulating the pathophysiology of TBI. Studies using the CB2R agonist, O-1966, in mice with TBI indicated that the administration of O-1966 attenuated the disruption of the blood-brain barrier and neuronal degeneration [194], and induced acute neuroprotective effects [195], supporting a role of CB2Rs in the management of TBI. There are also reports showing an increase in the expression of CB2Rs in mice with TBI associated with edema neurologic deficits. In that study, the authors found a positive correlation between the expression of CB2Rs and TBI [59]. In another study aimed at evaluating the potential effects of the CB2R agonists, HU-910 and HU-914, in the pathophysiology of TBI in mice, Magid et al. [196] demonstrated an enhanced neuroprotection and neurobehavioral recovery. In a recent study, the selective CB2R agonist, JWH133, protected white matter injury via PERK signaling in a rat model of traumatic brain injury [197].

5. Conclusions and Future Therapeutic Perspectives

The debunking of the myth that CB2Rs are only found in the "periphery" and the absence of intoxicating effects of these receptors significantly increased the interest in the investigation of these receptors as a therapeutic target in neuropsychiatric and neurodegenerative disorders. Currently, we cannot completely be satisfied with the partially effective treatments for most of these disorders, and hence more research is warranted for new therapeutic targets using novel strategies, including artificial intelligence (AI), that might have better prediction and therapeutic outcomes with minimal adverse effects. 

The rapid explosion of cannabinoid research may also transform the current landscape by using in vitro and in vivo technologies that will enhance our understanding of the potential role of CBRs in neuropsychiatric and neurodegenerative disorders. Despite the recent progress, the withdrawal of the FAAH inhibitor during clinical trials and the adverse effects due to the anti-obesity CB1R antagonist have engendered cautionary approaches in clinical trials. It is encouraging that clinical trials targeting CB2R, and the approval by the Food and Drug Administration (FDA) of nabiximols for epileptic seizures, are turning the targeting components of the CB2R-ECS into a pharmacotherapeutic strategy. 

The findings included in this review showed that CB2Rs are highly expressed in neuropsychiatric and neurodegenerative disorders, and that selective CB2R ligands have promising effects on the symptomatic management of these disorders. Additional studies are required to evaluate the involvement of CB2Rs in these disorders using the full range of tools that are available to study the CB2Rs and their selective ligands in animal models as well as in controlled clinical trials. Such future studies must include translational and clinical profiles and in vivo and in vitro models expressing human CB2Rs. Furthermore, a careful evaluation of the side effects associated with the chronic treatment of CB2R ligands will provide further insights into the potential role of CB2Rs in regulating neurophysiological and behavioral functions. The growing research interests in eCBome, the disturbances in its regulation, altered levels of eCBs, and discoveries of associated genetic polymorphisms provide targets for therapeutic intervention in neuropsychiatric and neurodegenerative disorders. Indeed, the densities of eCB receptors and the levels of eCBs have been suggested as possible biomarkers in neuropsychiatric disorders. 

With the increasing evidence that CB2Rs are involved in the brain, the functional role of the CB2R neuro-immune axis in pathophysiological signaling in the development of psychiatric disorders warrants further investigation. It is also noteworthy that the determination of the crystal structures of CB1R and CB2R reveals a yin-yang relationship and a functional profile of CB2R antagonism versus CB1R agonism [43,133,198]. This highlights another area where CB1R and CB2R seem likely to work both independently and/or cooperatively, and that will benefit from the development of critical medical applications. There are limitations and concerns regarding the use of CB2R medication for neurological disorders, as they are abundantly expressed in the periphery and may have peripheral side effects, while they may be useful in CNS disorders associated with neuroinflammation. 

It should be emphasized that a direct pharmacologic or genetic manipulation of the ECS might produce an effect different than the ones produced by phytocannabinoids. Further, research evaluating the numerous compounds in cannabis, along with terpenes and flavonoids, will add to our understanding of this natural eCBome in neuropsychiatric and neurodegenerative disorders and contribute to novel biomarkers and therapeutic agents.

Author Contributions: B.G.K. searched the literature and wrote the first and subsequent drafts of the manuscript. E.S.O. supervised and revised the manuscript. H.I. and Y.H. assisted in the literature research and in writing the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding: the University of Yamanashi and the Tokyo Metropolitan Institute of Medical Science supported the work and collaborative research by Dr. Ishiguro and Dr. Horiuchi. The research in Dr. Onaivi's group along with Dr. Berhanu Kibret is supported by NIAAA-NIH grant AA027909, William Paterson University, and the Dean of CoSH, Dr. Venkat Sharma. The CoSH funds support students and the Animal Laboratory facility.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.

Conflicts of Interest: The authors declare that there is no potential conflict of interest.

Abbreviations

6-OHDA, 6-hydroxydopamine; AC, adenylyl cyclase; AD, Alzheimer's disease; AEA, anandamide; AI, artificial intelligence; ALS, Amyotrophic lateral sclerosis; AN, anorexia nervosa; APP, amyloid precursor protein; ASD, autism spectrum disorder; Aβ, β-amyloid; BCP, β-caryophyllene; BN, bulimia nervosa; CB1R, cannabinoid type 1 receptor; CB2R, cannabinoid type 2 receptor; CBD, cannabidiol; CMS, chronic mild stress; CNS, central nervous system; CPP, conditioned place preference; D1Rs, dopamine type 1 receptors; EAE, autoimmune encephalomyelitis; eCBome, endocannabinoidome; eCBs, endocannabinoids; ECS, endocannabinoid system; ERK, 1/2extracellular signal-regulated kinase; FDA, food and drug administration; GIT, gastrointestinal tract; GPCRs, G-protein coupled receptors; HD, Huntington's disease; JNK, Jun N-terminal protein kinase; Kir, inwardly rectifying potassium currents; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MDA7, 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MS, multiple sclerosis; NAc, nucleus accumbens; NITyr, N-linoleyltyrosine; NMDA, N-methyl-D-aspartate; PD, Parkinson's disease; PEA, palmitoyl ethanolamide; PI3K, phosphoinositide 3-kinase; PPI, pre-pulse inhibition; PTZ, pentylenetetrazol; ROT, rotenone; TBI, traumatic brain injury; TH, tyrosine hydroxylase; TMEV- IDD, Theiler murine encephalomyelitis virus- induced demyelinating disease; VTA, ventral tegmental area; ∆ 9 -THC, Delta-9-tetrahydrocannabinol.

References

1. Basavarajappa, B.S.; Shivakumar, M.; Joshi, V.; Subbanna, S. Endocannabinoid system in neurodegenerative disorders. J. Neurochem. 2017, 142, 624–648. [CrossRef] [PubMed] 

2. Di Marzo, V. The endocannabinoidome as a substrate for non-euphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders. Dialogues Clin. Neurosci. 2020, 22, 259–269. [CrossRef] 

3. Pertwee, R.G.; Ross, R.A. Cannabinoid receptors and their ligands. Prostaglandins Leukot. Essent. Fat. Acids 2002, 66, 101–121. [CrossRef] [PubMed] 

4. Scotter, E.L.; Abood, M.E.; Glass, M. The endocannabinoid system is a target for the treatment of neurodegenerative disease. Br. J. Pharmacol. 2010, 160, 480–498. [CrossRef] [PubMed] 

5. Munro, S.; Thomas, K.L.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993, 365, 61–65. [CrossRef] 

6. Galiègue, S.; Mary, S.; Marchand, J.; Dussossoy, D.; Carrière, D.; Carayon, P.; Bouaboula, M.; Shire, D.; LE Fur, G.; Casellas, P. Expression of Central and Peripheral Cannabinoid Receptors in Human Immune Tissues and Leukocyte Subpopulations. Eur. J. Biochem. 1995, 232, 54–61. [CrossRef] 

7. Brown, S.M.; Wager-Miller, J.; Mackie, K. Cloning and molecular characterization of the rat CB2 cannabinoid receptor. Biochim. Biophys. Acta (BBA) Gene Struct. Expr. 2002, 1576, 255–264. [CrossRef] 

8. Griffin, G.; Wray, E.J.; Tao, Q.; McAllister, S.D.; Rorrer, W.K.; Aung, M.; Martin, B.R.; Abood, M.E. Evaluation of the cannabinoid CB2 receptor-selective antagonist, SR144528: Further evidence for cannabinoid CB2 receptor absence in the rat central nervous system. Eur. J. Pharmacol. 1999, 377, 117–125. [CrossRef] 

9. Poso, A.; Huffman, J.W. Targeting the cannabinoid CB2 receptor: Modelling and structural determinants of CB2 selective ligands. Br. J. Pharmacol. 2008, 153, 335–346. [CrossRef] 

10. Brusco, A.; Tagliaferro, P.; Saez, T.; Onaivi, E.S. Postsynaptic localization of CB2 cannabinoid receptors in the rat hippocampus. Synapse 2008, 62, 944–949. [CrossRef]

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