New Insights And Potential Therapeutic Targeting Of CB2 Cannabinoid Receptors in CNS Disorders Part 2

4.1.2. Depression and CB2R-ECS

As neuroinflammation is increasingly linked to a number of CNS disorders, and microglia cells, the brain's intrinsic immune cells, are the primary contributors to neuroinflammatory responses, we hypothesized that CB2Rs expressed in microglia and dopamine neurons modulate the behavioral responses in CB2R conditional knockout (cKO) mice. 

Neuroinflammation is an inflammatory response that affects our nervous system and destroys and damages nerve cells. This inflammatory response can have several negative effects on our brains, not the least of which is memory loss.

When our nervous system is damaged or affected by inflammation, our memory can be severely affected. Sometimes, we may forget our names or our favorite things, and our thinking can be affected, making it difficult to complete daily activities. These questions can cause frustration and worry, but we should not lose hope. Some approaches have had great success in helping us improve our memory and prevent neuroinflammation.

The first step is to promote the health of our nervous systems by keeping our bodies healthy. This includes keeping your body healthy by exercising, eating a healthy diet, and maintaining a normal sleep pattern. These measures will help increase the supply of oxygen and nutrients, which are important for keeping nerve cells functioning and repairing properly.

The second step is to enhance our brain function through continuous learning and participation in challenging activities. The stimulation of the brain by these activities will make it easier for us to remember and learn new information and may also help prevent neuroinflammation.

Finally, positive thinking and an optimistic attitude are also very important to keep our bodies and brains healthy. Research shows that positive thinking and positive emotions help reduce stress and anxiety, which is particularly important in mitigating the effects of neuroinflammation.

In summary, while neuroinflammation may affect our memory, we can prevent and mitigate its effects by staying healthy, engaging in challenging activities, and thinking positively. Please don't lose hope and believe that you can improve your life and brain function. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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The data from the studies revealed that CB2Rs in microglia and dopamine neurons are implicated in the neuro-immune modulatory effects of CB2Rs in mouse models of CNS disorders. In modeling depression in the mouse models, it is important to note that there are different types of depression with co-morbidities with mental and neurological disorders. 

There are limitations, and, to be useful, an animal model does not have to be a perfect replication of the disorder in terms of the predictive, face, and construct validity. For example, major depression is characterized by a depressed mood and anhedonia-a lack of pleasure-including other symptoms like reduced appetite and libido and disturbed sleep. 

While anhedonia can be modeled in rodent studies, a depressed mood is difficult to characterize. However, preclinical and clinical studies showed that the ECS is responsible for modulating depression, with reports that there is a negative correlation between the ECS signaling and depression [76]. 

The withdrawal of rimonabant, a CB1R antagonist, used for the treatment of obesity due to the risk of suicide and depression, has received increased interest as regards the role of CB1R in affecting mood and affective behavior. Some studies have investigated the role of CB1Rs in depression with more basic and clinical components, and factors like stress, the interaction with the endocrine system, and the use of cannabis and depression, with revealing outcomes. On the other hand, the involvement of the CB2R in affective disturbances has not received much attention [49]. 

Previous studies indicate that the overexpression of CB2R provoked a depression-like response. CB2xP mice (overexpressing CB2R) reduced the immobility time in acute models of depression (tail suspension and novelty-identification and feeding tests) [72]. Mutant (Cnr2−/− mice) developed a depressive-like behavior in the tail suspension test [56]. 

In line with this, the results found with the dopamine neuron cell-type-specific CB2R conditional knockout (DAT-Cnr2) mice demonstrated a depressive-like behavior indicated by an enhanced immobility time in the tail suspension and forced swimming tests [12]. However, a pharmacologic study using GW405833, a CB2R agonist, demonstrated that the acute administration of the agonist did not alter the immobility time in the forced swim test [77]. 

It is important to point out the validity and the mixed and conflicting responses in the use of some of these animal models of depression, that have been questioned in the scientific community. Nevertheless, the CMS is a commonly used animal model of depression, with similar behavioral and physiological effects observed in clinical settings in patients with depressive disorders [78–80]. 

The involvement of CB2R in depression was demonstrated in a study using mice subjected to CMS. The results showed that CB2R protein levels measured by immunoblotting in a whole brain extract were enhanced in mice subjected to CMS for 4 weeks [17,45]. However, another study showed a reduction in the level of CB2R mRNA in the hippocampus of mice subjected to CMS for 7–8 weeks, compared with non-stressed controls [72]. 

The contradiction might be due to differences in the time of exposure to CMS and variations in the brain regions used to measure the level of CB2R mRNA. The CMS protocol is characterized by a reduced intake of sucrose, used as a measure of anhedonia-like response, a hallmark of depression. Studies using transgenic mice that over-express the CB2R showed that there is no change in sucrose consumption and immobility time in mice subjected to a tail suspension test, respectively [72]. 

However, in another study done to evaluate the effect of CB2R ligands on sucrose consumption and the daily injection of JWH-015, a CB2R agonist, or AM630, a CB2R antagonist, did not alter the CMS-induced decreases in sucrose consumption [16,17]. 

Taken together, the results from the preclinical studies indicate the possible behavioral and molecular role played by CB2Rs in CMS. However, there is still limited literature on the role of CB2Rs in depression in humans. In one study conducted on Japanese patients with depression, the authors found that there is a high incidence of the Q63R polymorphism of the CB2R gene [16]. 

Furthermore, a reduction in the expression of the CB2R gene was documented in brain regions involved in regulating emotionality like the amygdala and the prefrontal cortex in a postmortem study performed in suicide patients [81] and in patients with major depression [82], indicating the role that CB2Rs could play in depression and the potential of these receptors as a new target for the treatment of depressive disorders, but this hypothesis requires additional modeling and clinical investigations.

4.1.3. Schizophrenia and CB2R-ECS

Schizophrenia is a type of psychotic disorder that is characterized by thinking disturbances, hallucinations, and delusions associated with genetic and epigenetic risk factors. Disturbances in the regulation of the ECS with altered levels of eCBs were associated with the development of schizophrenia. Indeed, the densities of eCB receptors and the levels of eCBs have been suggested as possible biomarkers in neuropsychiatric disorders [75]. 

Thus, the hypothesis on the role of cannabinoid self-medication, early exposure to cannabis, and the onset of psychosis in vulnerable adolescents has fueled a research interest in the changes in the ECS in neuropsychiatric disorders. Recently, there is also an increasing interest in the use of herbal and synthetic eCBs for the symptomatic management of schizophrenia [83]. 

Studies using animal models of schizophrenia indicated the involvement of CB2R in schizophrenia. Early maternal deprivation in rodents is a model for neurodevelopmental stress, and some reports indicate that maternal deprivation affects the ECS and that these changes may account for the proposed schizophrenia-like phenotype [84,85]. 

A study to evaluate the expression of CB1R and CB2R in the hippocampus showed that maternal deprivation induced a significant increase in CB2R immunoreactivity in the hippocampal areas, indicating the possible involvement of CB2Rs in neurodevelopmental mental illnesses such as schizophrenia [86]. The prepulse inhibition (PPI) test is one of the tests used to assess attention deficits associated with schizophrenia [13]. 

Methamphetamine and MK-801, a non-competitive N-methyl-Daspartate (NMDA) glutamatergic receptor antagonist, are two widely used animal models of schizophrenia that mimic the effects observed in schizophrenic individuals [87]. Studies showed that AM630, a CB2R antagonist, did not affect PPI on its own, but it did enhance the MK-801- and methamphetamine-induced decrease in PPI and the increase in locomotor activity [88]. 

Another study found that the administration of JWH015 in doses of 1, 3, and 10 mg/kg enhanced the PPI impairment caused by MK-801 [89]. CB2R's role in schizophrenia was investigated in genetically engineered mice. It was reported that Cnr2−/− mice were more susceptible to hyperlocomotion caused by acute cocaine exposure, as well as PPI and cognitive changes. Furthermore, in these mutant Cnr2−/− mice, treatment with the antipsychotic risperidone normalized the PPI readings [56,90]. Interestingly another study showed that CB2R is required for the antipsychotic effects of acetylcholine muscarinic 4 (M4) receptor agonists like UV0467154 [91]. 

This study found that stimulating the M4 receptors increased the release of eCBs while inhibiting dopamine release, implying that M4 agonists have a role in antipsychotic efficacy. As a result, inhibiting CB2Rs with the antagonist AM630 would prevent the antipsychotic effects of M4 agonists. Preclinical studies also showed that cannabidiol (CBD), another major phytocannabinoid, which is devoid of intoxicating effects, has antipsychotic properties [92–95] mediated by the activation of CB2Rs [96–98]. It should be pointed out that CBD is a non-intoxicating rather than a non-psychoactive constituent in the cannabis plant. 

According to the findings, CB2Rs play a significant role in the potentiation of antipsychotic medication effects. Clinical studies have also shown that CB2R is involved in schizophrenia. CNR2 gene expression was shown to be significantly reduced in the peripheral mononuclear blood cells of patients with schizophrenia [99]. In Japanese schizophrenia patients, the CNR2 polymorphisms rs12744386 and rs2501432 were found to be significant (Ishiguro et al., 2010), whereas the CNR2 polymorphisms rs2501432 and rs22229579 were found to be significant in the Han ethnic population of China [100]. 

These findings imply that CB2R plays a critical role in modulating psychotic symptoms. However, further controlled clinical trials are needed to determine the role of CB2Rs in the treatment or as an adjunctive strategy in schizophrenia.

4.1.4. CB2R-ECS in Addiction

The global drive and use of cannabis and cannabinoids for recreation and medicine requires a focus on the emerging complex eCBome in reward processing and drug addiction in emerging cannabis use disorders (CUDs). 

With the emergence of the COVID-19 pandemic, and the devastating global consequences, drug addiction especially the opioid epidemic and overdoses and death, increased alcohol consumption, and obesity are major concerns [66]. The discovery of this previously unknown but ubiquitous ECS, and the fact that CBRs are encoded in the human genome on chromosomes 1 and 6, have led to the changing landscape of cannabinoid research and provided scientific evidence of the potential therapeutic benefits of targeting the ECS. 

There are still gaps in our understanding, but the discovery of the expression of CB2Rs in brain regions involved in drug addiction, such as the ventral tegmental area (VTA), nucleus accumbens (NAc), amygdala, and hippocampus unraveled and encouraged the investigation of the role of CB2Rs in drug addiction [101]. Therefore, the increasing interest and attention on the CB2Rs as a target for the treatment of drug addiction is due in part to its neuro-immune functioning associated with the reward pathway. 

Pharmacologic and genetic studies showed that CB2Rs are involved in the effects of psychostimulants like cocaine, amphetamines, and methamphetamines. CB2R is involved in cocaine motor sensitization in studies employing genetically modified mice. Mice overexpressing CB2R in the (CB2xP) showed reduced hyperlocomotor effects in response to acute cocaine administration and were less susceptible to motor sensitization after repeated cocaine administration [102]. 

Interestingly, mice lacking the CB2R (Cnr2−/−), which have increased sensitivity to cocaine-induced hyperlocomotion, had the opposite effect [56]. A study aiming to evaluate the effects of psychostimulants in dopamine neuron CB2R conditional knockout (DAT-Cnr2 cKO) mice on locomotor activity showed that mice had increased cocaine-, amphetamine-, and methamphetamine-induced hyperactivity, without psychostimulant-induced sensitization when compared to wild-type controls. In addition, the authors reported that cocaine, amphetamines, and methamphetamines produced a robust conditioned place preference (CPP) in both DAT-Cnr2 cKO and wild-type mice [55]. 

In stark contrast, studies using JWH133 revealed a systemic and local administration of JWH133 into the NAc-blocked cocaine hyperlocomotion in mice [41,103]. In line with this, a study revealed that JWH133 inhibited cocaine and nicotine-induced CPP in wild-type mice [55]. However, in another investigation, AM630 was found to not affect the locomotor effects after an acute or repeated cocaine administration in rats [103,104]. 

These inconsistencies could be explained by differences in animal species and the methods utilized. Since cocaine produced place aversion rather than place preference in CB2xP animals, and these transgenic mice showed impairment in the acquisition of cocaine self-administration [102], CB2Rs appear to be implicated in the reinforcing features of cocaine. 

Evidence also showed that the intranasal or intra-accumbens administration of JWH133 prevented intravenous cocaine self-administration [41]. The involvement of CB2Rs in a model of addictive behavior has been demonstrated by the study using the natural CB2R agonist β-caryophyllene (BCP). The results showed that BCP attenuated methamphetamine self-administration in rats, which was partially blocked by AM630 [105]. The study also revealed that the deletion of CB2Rs blocked a low-dose BCP-induced reduction in methamphetamine self-administration. 

There are also investigations on the role of CB2Rs in the modulation of alcohol consumption and reward. The injection of BCP lowered the ethanol CPP and ethanol intake in mice, increased the voluntary ethanol consumption in the two-bottle paradigm, and provided an incentive to drink in the oral ethanol self-administration in the mutant Cnr2−/− mice [106,107]. In addition, a sub-chronic injection of JWH015 enhanced the alcohol intake in mice that had previously been exposed to chronic stress, with no impact in mice that had not been exposed to chronic stress [64,108]. 

A recent study also demonstrated that alcohol exposure during adolescence induced increases in the amygdala expression of the CB2Rs in rats [109]. A substantial incidence of the single nucleotide polymorphism R63Q in the CNR2 gene locus was observed in a cohort of Japanese alcoholic patients in clinical investigations [64]. This single nucleotide polymorphism causes a missense mutation in the first intracellular domain, which reduces the physiological responsiveness to CB2R ligands [101]. 

More recently, Navarrete et al. extensively compiled a significant appraisal of type-2 cannabinoid receptor involvement in the treatment of substance use disorders (SUDs), including alcohol and psychostimulants (cocaine and nicotine), with an emphasis on the CB2R species differences in the effects of the SUDs covered (198). They concluded that when combined with existing options, the development of pharmacotherapeutic agents targeting the CB2Rs might offer novel approaches [110]. 

It is noteworthy that preclinical investigations show that CB2R ligands can modulate the reward system and increase the understanding of neuroinflammation in CNS disorders. All the above data support the role of CB2Rs in modulating the addictive effects of alcohol and different psychostimulants, indicating that CB2Rs might be targeted in the treatment of drug addiction. 

Therefore, there is now an increased focus and interest in CB2Rs in drug and alcohol addiction, with increasing reports indicating their functional expression not only in reward circuits but also in the CB2R-neuro-immune crosstalk and signaling in neuropsychiatric disorders.

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