Role of Cannabinoid Receptors in Psychological Disorder

Psychological disorders are responsible for the largest proportion of the global burden of disease worldwide (Whiteford et al., 2015). It has been suggested that by 2030, depression will be the leading cause of disease burden globally (Lépine & Briley, 2011). Uncontrolled excitotoxicity and neuroinflammation contribute to cell death and damage in neurological and neuropsychiatric diseases, including some that are related to stress exposure (neurodegenerative diseases, depression, posttraumatic stress disorder, and schizophrenia) (Tay et al., 2017). Cannabis is touted to effectively attenuate a wide range of conditions, including asthma, inflammatory bowel disease, glaucoma, multiple sclerosis, menstrual cramps, AIDS, nausea, and cancer (Bruni et al., 2018). Delta-9tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis, and most, if not all, of the effects associated with the use of cannabis, are caused by THC (Kimura et al., 2019). Beyond these effects on physical conditions, cannabis has been reported to improve neurocognitive and psychiatric conditions, such as Alzheimer's disease, anxiety disorders, and bipolar disorder (Abizaid et al., 2019; Sarris et al., 2020; Burggren et al., 2019). The endocannabinoid system (ECS) plays key modulatory roles during synaptic plasticity and homeostatic brain processes (Lu & Mackie, 2016). This review discusses some relationships between the cannabinoid (CB1 and CB2) receptors and their ligands with the nervous system in health and disease. We will introduce the two major receptors, focusing on the CB1 receptors due to their high expression levels in the CNS. Their endogenous ligands or endocannabinoids (ECB) and some synthetic mimetics that activate and modulate their signaling; the signaling pathways that connect this Role of Cannabinoid Receptors in Psychological Disorder


INTRODUCTION
Psychological disorders are responsible for the largest proportion of the global burden of disease worldwide (Whiteford et al., 2015). It has been suggested that by 2030, depression will be the leading cause of disease burden globally (Lépine & Briley, 2011). Uncontrolled excitotoxicity and neuroinflammation contribute to cell death and damage in neurological and neuropsychiatric diseases, including some that are related to stress exposure (neurodegenerative diseases, depression, posttraumatic stress disorder, and schizophrenia) (Tay et al., 2017).
Cannabis is touted to effectively attenuate a wide range of conditions, including asthma, inflammatory bowel disease, glaucoma, multiple sclerosis, menstrual cramps, AIDS, nausea, and cancer (Bruni et al., 2018). Delta-9tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis, and most, if not all, of the effects associated with the use of cannabis, are caused by THC (Kimura et al., 2019). Beyond these effects on physical conditions, cannabis has been reported to improve neurocognitive and psychiatric conditions, such as Alzheimer's disease, anxiety disorders, and bipolar disorder (Abizaid et al., 2019;Sarris et al., 2020;Burggren et al., 2019). The endocannabinoid system (ECS) plays key modulatory roles during synaptic plasticity and homeostatic brain processes (Lu & Mackie, 2016).
This review discusses some relationships between the cannabinoid (CB1 and CB2) receptors and their ligands with the nervous system in health and disease. We will introduce the two major receptors, focusing on the CB1 receptors due to their high expression levels in the CNS.
Their endogenous ligands or endocannabinoids (ECB) and some synthetic mimetics that activate and modulate their signaling; the signaling pathways that connect this receptor to processes inside the cell; and the role of the CB system in the normally functioning CNS and its alteration or therapeutic modulation in a variety of disease states (Tanaka et al., 2020).

SYSTEM
Before discussing the ECS's functions, it is essential to understand its components. The ECS comprises cannabinoid receptors, endogenous ligands (binding molecules) for those receptors, and enzymes that synthesize and degrade the ligands (Stasiulewicz et al., 2020).
The most well-known cannabinoid receptors are CB1 and CB2. Studies in the early 1990s provided initial evidence of the existence and purpose of CB1 and CB2 receptors. Both types of cannabinoid receptors are found throughout the entire body but are distributed differently (Zou & Kumar, 2018). The CB1 receptors are concentrated primarily in the Central Nervous System, are most highly expressed by the axons and presynaptic terminal of neurons in the amygdala, hippocampus, cortex, basal ganglia outflow tracts, and cerebellum (Castillo et al., 2012). In contrast, CB2 receptors are mainly found in the immune system (Turcotte et al., 2016).
However, CB1 receptors are also distributed in various peripheral areas like adipose (fat) tissue, and CB2 receptors are expressed to some degree in the brain (Howlett & Abood, 2017 (Wheatley et al., 2012). Binding induces a conformational change in the receptor, causing activation of a G protein docked to the inner face, which initiates a specific cellular process (Black et al., 2016).
In general, an agonist-bound receptor activates an appropriate G protein that promotes dissociation of GDP. The GPCR ligands fall into four categories depending on the nature of their interaction: agonists, antagonists, partial agonists, and inverse agonists (Weis & Kobilka, 2018). Agonists bind to the receptor and elicit a cellular response by causing a conformational change.
Antagonists bind, prevent agonists from binding, and do not elicit any response. A partial agonist is an intermediate class that, upon binding, does not invoke the complete agonist conformational change but still allows for partial activity. Simultaneously, they "block" the receptor from being available for full agonist binding.
When both a full agonist and partial agonist are present, the partial agonist acts as a competitive antagonist, producing a net decrease in the receptor's activation.
Inverse agonists bind to a receptor but induce a physiological response opposite to what would be expected from an agonist (Shahbazi et al., 2020;Berg & Clarke, 2018). The affinity of a ligand for the receptor is independent of the role: weakly binding full agonists and strongly binding partial agonists are both known (Buchwald, 2019;Patel et al., 2019).
Agonists targeting CB2 receptors have been proposed to treat or manage a range of painful conditions, including acute pain, chronic inflammatory pain, and neuropathic pain (Dhopeshwarkar & Mackie, 2014;Vučković et al., 2018;Donvito et al., 2018). The ECB system is primarily composed of two inhibitory GPCRs, CB1 and CB2, and  The neural mechanisms by which endocannabinoid signaling affects anxiety are not well understood, yet several mechanisms at the systems, synaptic, and molecular level can be posed based on available data. The majority of available data indicate that ECS has anxiolytic properties in both conditioned and unconditioned anxiety models and that these effects are more active during states of stress or high arousal (Stasiulewicz et al., 2020;Patel & Hillard, 2009). Endocannabinoid signaling's anxiolytic effects are mimicked by low doses of direct CB1 receptor agonists (Hill et al., 2018). Thus, data exploiting this phenomenon can be used to increase our understanding of the neural mechanisms subserving the endocannabinoid signaling system's anxiolytic actions (Patel & Hillard, 2009).
At the systems level, microinjections of low doses of the direct CB1 agonist THC into the prefrontal cortex (PFC) (Rubino et al., 2008), ventral hippocampus, and a dorsal periaqueductal gray area exert anxiolytic effects in the elevated plus-maze (Moreira et al., 2007). Stress relief and relaxation are frequently reported as drivers of cannabis use (Turna et al., 2017). These effects are blocked by the CB1 receptor antagonist AM251 (Boctor et al., 2007).
Pharmacological inhibition of FAAH within the PFC produces CB1 receptor-dependent, anxiolytic effects, and over-expression of FAAH (which reduces local Narachidonoylethanolamine levels) causes the anxiogenic effect in the elevated plus-maze (Navarrete et al., 2020;Lutz et al., 2015).
In contrast to the PFC and hippocampus, very low THC doses produce only anxiogenic effects when administered into the basolateral amygdala (BLA); this was also dependent upon CB1 receptor activation. These data suggest that the PFC and hippocampus are likely anatomical sites of action that subserve ECS's anxiolytic effects. More specifically, the balance of ECS in favor of an increase in the PFC plus hippocampus and reduced signaling in the amygdala could be required for maximal anxiolytic effects (Patel & Hillard, 2009 (Herman et al., 2016).
Recent studies strongly suggest that the ECS's primary role is to dampen HPA axis activation by stress and allow for appropriate stress recovery (Stephens & Wand, 2012).
These findings are consistent with the data obtained in rodents described above that ECS inhibition is generally pro-depressive. Simultaneously, its activation results in an anti-depressant phenotype and leads to the hypothesis that the HPA axis's dampening is the mechanism by which ECS interacts with depression.
However, HPA axis inhibition does not entirely explain ECS's effects to alter coping behaviors in the forced swim assay (Barden, 2004

CANNABINOID RECEPTOR IN EPILEPSY
Cannabidiol good affinity at the plausible concentration for 5-HT1A and 5-HT2A receptors, and 5-HT2A receptors act as a target for fenfluramine, a drug for which some evidence supports efficacy drug-resistant epilepsies such as Dravet syndrome (Ceulemans et al., 2012). A minimal number of studies have reported changes in 5-hydroxytryptamine (5-HT) receptor expression and function in people with epilepsy, although it remains unclear whether this is a consequence of the disease or a component of pathogenesis. Thus, while 5-HT involvement in pathogenesis remains uncertain, some 5-HT receptor subtypes may represent a valid therapeutic target in epilepsy through which CBD could be acting (Theodore et al., 2007;Theodore et al., 2012). Glycine receptor (GlyR) is predominantly expressed in the CNS, neuronal cells, brainstem, and spinal cord, and there is much less evidence of their role in disorders of the cerebrum, such as epilepsy. However, recent research in rodent species has shown significant, functional GlyR expression in cortex and hippocampus at least up to postnatal day 14, where they serve to modulate neuronal network function (Avila et al., 2013), and emerging evidence suggests a role in hyperexcitability disorders (Harvey et al., 2008). These findings suggest that investigation of GlyR function in healthy and epileptic, mature human cortex is warranted in order to lend further credence to GlyR-mediated antiepileptic effects of CBD.

ALZHEIMER'S DISEASE
Alzheimer's disease (AD) is the most common neurodegenerative disease in Western Europe, and a significant public health problem as the number of cases increases with the aging of the population. It manifests with a progressive decline in memory and intellectual abilities, impoverishment of language, disorientation, and behavioral skills (Mayeux & Stern, 2012). The AD is also characterized by enhanced beta-amyloid peptide   (2)