Review
The endocannabinoidome in neuropsychiatry: Opportunities and potential risks

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Abstract

The endocannabinoid system (ECS) comprises two cognate endocannabinoid receptors referred to as CB1R and CB2R. ECS dysregulation is apparent in neurodegenerative/neuro-psychiatric disorders including but not limited to schizophrenia, major depressive disorder and potentially bipolar disorder. The aim of this paper is to review mechanisms whereby both receptors may interact with neuro-immune and neuro-oxidative pathways, which play a pathophysiological role in these disorders. CB1R is located in the presynaptic terminals of GABAergic, glutamatergic, cholinergic, noradrenergic and serotonergic neurons where it regulates the retrograde suppression of neurotransmission. CB1R plays a key role in long-term depression, and, to a lesser extent, long-term potentiation, thereby modulating synaptic transmission and mediating learning and memory. Optimal CB1R activity plays an essential neuroprotective role by providing a defense against the development of glutamate-mediated excitotoxicity, which is achieved, at least in part, by impeding AMPA-mediated increase in intracellular calcium overload and oxidative stress. Moreover, CB1R activity enables optimal neuron-glial communication and the function of the neurovascular unit. CB2R receptors are detected in peripheral immune cells and also in central nervous system regions including the striatum, basal ganglia, frontal cortex, hippocampus, amygdala as well as the ventral tegmental area. CB2R upregulation inhibits the presynaptic release of glutamate in several brain regions. CB2R activation also decreases neuroinflammation partly by mediating the transition from a predominantly neurotoxic “M1” microglial phenotype to a more neuroprotective “M2” phenotype. CB1R and CB2R are thus novel drug targets for the treatment of neuro-immune and neuro-oxidative disorders including schizophrenia and affective disorders.

Introduction

The endocannabinoid system (ECS) has classically been described as a lipid-based signalling system comprised of two cognate endocannabinoid receptors referred to as CB1R and CB2R, together with their arachidonic acid-derived agonists; 2-arachidonoyl glycerol (2-AG) and anandamide (AEA), known as endocannabinoids [1]. In addition, the enzymes responsible for the biosynthesis of endocannabinoids, namely N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), diacylglycerol lipase-α and -β, and for their metabolism, namely fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) comprise the classical ECS [2], [3], [4]. More recently, however, the concept of this system has been expanded to include other receptors, which are targets for AEA, such as the G protein-coupled receptor 55 (GPR-55), the transient receptor potential cation channel subfamily V member 1 (TRPV1) as well as Peroxisome Proliferator-Activated Receptors (PPARs). Other lipid classes, namely the N-acylethanolamines and N-acyldopamines are also increasingly considered to possess endocannabinoid-like properties, which may also activate GPR-55, TRPV1 and PPAR, and, in many cases, CB1Rs and CB2Rs [5], [6], [7], [8], [9], [10]. The molecular players involved in the wider ECS known as the ‘endocannabinoidome’ are depicted in Fig. 1.

The ECS modulates the activity of γ-aminobutyric acid (GABA)-ergic, glutamatergic, serotonergic and dopaminergic pathways in the central nervous system (CNS). In addition, it regulates long-term potentiation (LTP) and long-term depression (LTD), thereby regulating synaptic plasticity and consequently learning and memory [11]. The ECS also plays a central role in the prevention of glutamate-mediated N-methyl-D-aspartate (NMDA) receptor excitotoxicity and neural damage in an inflammatory milieu [12], [13]. This system also plays a major regulatory role in neuron-glial cross-talk [14], [15]. Furthermore, the endocannabinoidome may prevent and inhibit neuroinflammation and may also play a fundamental role in the maintenance of the integrity and function of the blood-brain barrier (BBB) [16], [17]. Other important functions of the ECS in the central nervous system (CNS) include the modulation of brain reward function, emotion regulation [18], [19], nociception [20], [21] and sleep homeostasis [22].

The ECS also exerts a plethora of modulatory functions in other biological systems, with major regulatory roles in the neuroendocrine system, hypothalamic-pituitary-adrenal (HPA) axis activity as well as in the neuroendocrine response to stress [23], [24]. Furthermore, this system modulates appetite [21], [25], and regulates responses to peripheral inflammation and infection [26].

It also regulates glucose metabolism in the liver and pancreas [27], [28]. In addition, it modulates lipogenesis and adipogenesis in adipose tissues [29], thereby contributing to the prevention of insulin resistance (IR), the metabolic syndrome, obesity and type 2 diabetes (T2D). Furthermore, the ECS plays a major physiological role in the gastrointestinal (GI) tract, influencing parameters such as GI motility and communication within the gut-brain axis [30], [31]. The effects of the ECS in the periphery extend to the cardiovascular system [32], [33], including the inhibition of atherosclerosis [34], regulation of lung function [35] as well as the maintenance of renal system homeostasis [36]. Therefore, dysfunction of the ECS may be associated with the onset of IR, the metabolic syndrome, obesity, T2D, atherosclerosis, cardiovascular disease, non-alcoholic fatty liver disease and renal disease [36], [37], [38], [39], [40], [41].

A dysfunctional ECS in the CNS has also been increasingly implicated in the pathophysiology of neuropsychiatric disorders, such as Alzheimer’s disease [42], Parkinson’s disease [43], Huntingdon’s disease [44], multiple sclerosis [45] and amyotrophic lateral sclerosis. ECS dysregulation is also apparent in individuals with schizophrenia (SZ) [46], anxiety disorders (AD) [47], [48], major depressive disorder (MDD) [49] and potentially bipolar disorder (BD). Neuro-immune and neuro-oxidative pathways have also been increasingly implicated in the development of these disorders [50], [51], [52]. These latter pathways are involved in neurocognitive impairments, behavioural symptoms, and neuroprogression, which characterize a significant number of individuals experiencing these chronic neuro-psychiatric disorders [49–51].

Reduced or dysregulated expression and function of CB1Rs in multiple regions of the brain in chronic SZ patients has been reported by several authors in vivo and post mortem [53], [54], [55], [56] as reviewed in detail elsewhere [57]. Decreased availability and/or increased CB1R binding are among the most replicated findings in medication-free individuals with first-episode psychosis [58], [59], [60]. Importantly, the degree of CB1R unavailability and increase in binding has been associated with increased symptom severity [58], [59], [60]. Decreased CB1R availability also correlated with increased levels of glutamate [61]. Several studies have reported associations between single-nucleotide polymorphisms in cannabinoid-related genes and fear states, anxiety and stress-related disorders (as reviewed in ref. [62]). Together these studies suggest that genetic alterations in the ECS could predict the occurrence of ADs. There are also data to suggest that CB1R receptor dysfunction may play a role in the pathophysiology of MDD [63] although the precise mechanisms involved are difficult to determine and the data appear to be influenced by gender, medication use as well as duration of illness [63], [64], [65] (see ref. [66] for a review). However, once again a pattern of decreased CB1R availability and increased binding appears to be the most consistent finding [67], [68]. It is noteworthy that a recent meta-analysis concluded that there was no relationship between common CB1R gene polymorphisms and the development of MDD, but polymorphisms in CB2R showed promise for and association with MDD [69].

While there has been a great deal of research investigating the role of endocannabinoid receptors in SZ, AD and MDD, curiously there has been a dearth of research in this area within the context of BD [70]. Consequently, while there is some evidence to suggest that CB1R and CB2R malfunction may be involved in the pathophysiology of this illness [63], [66], [71], evidence is quantitatively and qualitatively limited.

The pattern of data regarding endocannabinoid status in the brain and periphery follows a similar pattern. In the case of SZ there are consistent findings demonstrating elevated levels of AEA in all regions of the brain in all phases of the illness (see review by Minichino, et al. [72]). Similarly, researchers investigating peripheral endocannabinoid levels have consistently reported elevated levels of AEA and 2-AG, which normalise during clinical remission [60], [73]. Endocannabinoid signalling is also well positioned to modulate neuronal activity and synaptic plasticity in the fear and anxiety circuitry (see ref. [48] for a review). Furthermore, several gene variants associated with endocannabinoid transmission (e.g., FAAH, CB1R) have been linked to AD [74] and trauma-related disorders [75]. However, the data are inconsistent in the case of MDD with increased and decreased levels being reported depending on gender, antidepressant drug treatment, effects of electroconvulsive therapy, exercise status and smoking history [76], [77], [78], [79], [80]. Once again, there is a dearth of data relating to endocannabinoid levels in BD [81].

Normalising CB1R activity would appear to be a desirable neurotherapeutic avenue for SZ, AD, MDD, and, arguably, BD. However, historical evidence suggests that the pharmacological manipulation of CB1R expression and/or levels is not without hazards. Agonism or inverse agonism of CB1Rs have been associated with serious psychiatric adverse effects, such as psychosis and/or panic attacks, whilst antagonism to those receptors would arguably impair CNS homeostasis [82], [83], [84], [85].

CB2Rs appear to be most prevalent on postsynaptic somatodendritic areas [86], [87], [88] and the activation of postsynaptic CB2Rs usually inhibits neuronal excitability [89], [90]. For example, their activity inhibits the firing and excitability of dopaminergic neurons in the ventral tegmental area (VTA) [86], [87]. CB2R activity also modulates the synaptic plasticity of CA1 neurons as well as neural plasticity and synchronisation of CA3 neurons in the hippocampus [86], [87], thereby regulating working memory and anxiety levels [91]. Importantly, while the bulk of research in this area has focused on the role of postsynaptic CB2Rs in the regulation of dopamine-related behaviours, such as anxiety, pain, and addiction, these receptors are also involved in the suppression of GABAergic and glutamatergic neurotransmission [92], [93], [94], [95]. The mechanism underpinning the reduction in GABAergic neurotransmission effected by post synaptic CB2Rs appears to occur via the inhibition of GABA receptors [94] However, the mechanisms enabling the CB2R-mediated inhibition of glutamatergic neurotransmission remain unclear [95]. In addition, the relationship between CB1Rs and CB2Rs in the regulation of neurotransmission is likely to be complex since CB1Rs are predominantly expressed on post-synaptic terminals, whilst CB2Rs may also be present in pre-synaptic terminals [96], [97], [98], [99]. The role of CB2Rs in the regulation of neurotransmission under physiological conditions is difficult to determine, since the expression of such receptors are low in such circumstances [86]. Nevertheless, the expression of CB2Rs in post- and pre-synaptic regions are massively increased in states of anxiety, pain, addiction and neurotoxicity[100], [101], [102] (see also ref. [86] for a review). In addition, results from animal studies suggest that CB2R antagonism may hold promise for the treatment of these conditions [100], [103], [104] (see ref. [105] for a review). Hence, the role of CB2Rs in regulating neurotransmission in those pathophysiological scenarios is likely to be meaningful. The mechanisms underpinning, such an increase in CB2R expression are the subject of intense research efforts, and are further considered further below in the context of activated microglia (i.e., neuroinflammation).

The manipulation of CB2R receptor activity and/or expression has not been associated with adverse biobehavioural effects and its upregulation has been associated with profound anti-inflammatory and neuroprotective effects in the CNS and restoration of homeostasis in the periphery [106], [107]. Thus, therapeutic approaches aimed at upregulating this receptor would hold more promise as potentially safe therapeutic approach for diverse neuropsychiatric conditions. This is in marked contrast to the neuropsychiatric adverse effects discussed above following the modulation of CB1Rs in some circumstances.

However, a review of the extant literature reveals that the mechanisms involved in the anti-inflammatory effects following CB2R up-regulation are under-discussed, and we are not aware of published research in this area. Accordingly, this paper aims to add to the literature in this domain as well. Currently, most research investigating the regulation of the ECS has focused on the interplay between endocannabinoids and CB1Rs (e.g. see Zou and Kumar [108]). In addition, we will critically discuss the potential role of the endocannabinoidome in neuropsychiatry as well as the putative therapeutic benefits and threats of the manipulation of this system as novel treatment targets for neuropsychiatric conditions.

Section snippets

Synthesis of 2-AG

The most common route of 2-AG synthesis involves the production of 2-AG from diacylglycerol (DAG) precursors by the action of 2-DAG lipases, namely diacylglycerol lipase-α and -β (DAGLα and DAGLβ, respectively) [109], [110], [111]. DAGLα is the predominant isoform in the brain [112], [113], and most evidence suggests that DAGLα-mediated 2-AG formation is the predominant pathway for the synthesis of this endocannabinoid in the CNS [114].

DAG may be produced by two main pathways. The first

CB1R-mediated G protein signalling

In G-protein coupled signalling, activated CB1Rs function as a guanine nucleotide exchange factor and promote the exchange of GDP for GTP, which is normally bound to the Gα subunit in the inactive heterotrimeric Gαβγ complex [108], [194], [195]. The presence of GTP is the main player in rendering the complex inactive and in an associated state, thus inhibiting G-coupled signalling [196], [197]. Hence, the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) leads to the

CB2R signalling

There is a wealth of evidence from in vitro and in vivo studies involving animal models of various inflammatory illnesses demonstrating Gαi/o coupling following agonist-mediated CB2R activation [361], [362]. Unsurprisingly, such coupling leads to an inhibition of AC, decreased levels of cAMP and increases in MAPKs, most notably ERK1/2 [361], [363], [364], [365]. Activation of ERK1/2 has been cited as the pivotal outcome of CB2R activation [366], [367], [368]. However, there is also evidence

Conclusion and forward directions

The ECS is a retrograde lipid neurotransmitter system with complex interactions and modulatory effects on various neurotransmitter (GABAergic, glutamatergic, serotonergic and dopaminergic) systems as well as other biological pathways such as HPA-axis and inflammation involved in regulation of CNS and peripheral functions [11], [16], [17], [23], [24]. Hence, the dysregulation of the ECS has been linked to pathophysiological processes of neuropsychiatric disorders including neurodegenerative [42]

Declaration of Competing Interest

GM, KW, PA, CCB, MM, BKP, and AFC have nothing to disclose. SK is supported by the University of Toronto Department of Psychiatry Academic Scholar Awards and the Labatt Family Innovation Fund in Brain Health. SK received honorarium for past consultation from EmpowerPharm. MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical

Acknowledgement

MB is supported by a NHMRC Senior Principal Research Fellowship (1059660 and 1156072).

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