Cannabinoid 1 and 2 receptors

CB1Rs are mainly in the brain, particularly in the substantia nigra, the basal ganglia, limbic system, hippocampus and cerebellum, but are also expressed in the peripheral nervous system, liver, thyroid, uterus, bones and testicular tissue [Russo and Guy, 2006; Pagotto et al. 2006; Pertwee, 2006]. CB2Rs are mostly expressed in immune cells, spleen and the gastrointestinal system, and to some extent in the brain and peripheral nervous system [Izzo, 2004; Pertwee, 2006]. Interestingly, both CB1 and CB2Rs are also found in human placenta and have been shown to play a role in regulating serotonin transporter activity [Kenney et al. 1999]. Indeed further research has revealed that the endocannabinoid system also plays a significant role in various aspects of human reproduction [Taylor et al. 2010].

In the brain, CB1Rs are found at the terminals of central and peripheral neurons, where they mostly mediate inhibitory action on ongoing release of a number of excitatory and inhibitory dopaminergic, gamma-aminobutyric acid (GABA), glutamatergic, serotoninergic, noradrenalin and acetylcholine neurotransmitter systems (Figure 1). Because of the involvement of these systems they affect functions such as cognition, memory, motor movements and pain perception [Howlett et al. 2002]. The release of endocannabinoids, such as AEA and 2-AG, from the postsynaptic sites to the synaptic cleft occur in response to elevation of intracellular calcium and they then act as retrograde neurotransmitters on presynaptically located CB1Rs to maintain homeostasis and prevent the excessive neuronal activity [Howlett et al. 2002; Terry et al. 2009]. They are then rapidly removed from the extracellular space by cannabinoid transporters, often referred to as anandamide membrane transporters, which facilitate their breakdown by internalizing the molecule and allowing access to fatty acid amide hydrolase [Pertwee, 2010]. Despite its significance in the endocannabinoid system, little is known about the cannabinoid transporters.

When cannabis is used, d-9-THC as a partial agonist binds to CB1R and acts in a less selective manner in inhibiting the release of neurotransmitters normally modulated by endocannabinoids such as AEA and 2-AG. It has been putatively suggested that it may also increase the release of dopamine, glutamate and acetylcholine in certain brain regions, possibly by inhibiting the release of an inhibitory neurotransmitter like GABA onto dopamine, glutamate or acetylcholine-releasing neurons [Bhattacharyya et al. 2009a] (Figure 2).

Figure 2.

CB1 receptors – effects of endocannabinoids and d-9-THC Release of Anandamide (AEA) and 2- arachidonoylglycerol (2-AG) to inhibit glutamate (Glu), Gamma-aminobutyric acid (GABA), acetylcholine (Ach), dopamine, noradrenaline (NA) and serotonin (5-HT). …

However, the functionalities of the CB1Rs are not always straightforward due to complex interactions with the other neurotransmitter systems. These are related to CB1Rs and CB2Rs being members of the super family of G-protein-coupled receptors (GPCRs) [Pertwee et al. 2010]. GPCRs sense an external molecule outside the nerve cell and by contact with the molecule can signal transduction pathways, which ultimately lead to cellular responses. External ligands such as d-9-THC, various synthetic compounds and endocannabinoids such as anandamide can activate these receptors [Pertwee et al. 2010]. Interestingly some alkylamides from the Echinacea plant can also bind to the CB2Rs even more strongly than the endogenous cannabinoids [Raduner et al. 2006]. The mechanism of action for CBD is not yet clear, as this compound does not bind to CB1Rs or CB2Rs [Tsou et al. 1998; Hayakawa et al. 2008].

Normally GPCRs are linked together to form a receptor complex. However, the signalling effects can be complex due to CB1Rs forming heteromers, which can be defined as having different parts such as subunits, with two or more other GPCRs, particularly if they are densely expressed in the same neuron. For instance, a CB1R can form a heteromer with dopamine D2 receptor, or in another instance it can also form a heteromer with two other receptors such as dopamine D2 and adenosine A2A [Navarro et al. 2008]. Interestingly, as a result, ligand bindings can produce unexpected pharmacological effects. For instance, in a heteromer complex, not only the antagonist of CB1R but also the other receptor antagonist can block the inhibitory effect of CB1R agonist. This has been demonstrated by Marcellino and colleagues when the CB1R antagonist rimonabant and the specific A2AR antagonist MSX-3 blocked the inhibitory effect of CB1 agonist on D2-like receptor agonist induced hyperlocomotion in rats [Marcellino et al. 2008]. Receptor heteromers provide better understanding of how these different neurotransmitter systems interact with each other. Compelling evidence for the existence of CB1R heteromers in striatal dendritic spines of striatal GABAergic efferent neurons, particularly at a postsynaptic location, has also been reported [Ferré et al. 2009]. The authors propose that it is likely that functional CB1–A2A–D2 receptor heteromers can be found in the dendritic spines of GABAergic enkephalinergic neurons, where they are highly coexpressed, and their analysis provides new information on the role of endocannabinoids in striatal function, which can be considered as retrograde signals that inhibit neurotransmitter release. Further evidence for the existence of D2 and CB1Rs in ventral striatum is provided by electron microscopy analysis, which confirms the relevance to the rewarding and euphoric, as well as motor effects produced by cannabis, by enhancing dopamine levels particularly in the nucleus accumbens [Pickel et al. 2006]. CB1R expression in the striatum and their role in differential signalling between different developmental stages and sensorimotor and associative/limbic circuits have also been demonstrated in a recent study [van Waes et al. 2012].

Most recently it has been shown that CB2Rs form heteromers with CB1Rs in the brain and the agonist coactivation of CB1Rs and CB2Rs results in negative crosstalk in AKT1 phosphorylation and neurite outgrowth [Callénet al. 2012]. The authors point out that there is a bidirectional cross antagonism which involves the antagonists of either receptor to block the other. It is suggested that these data illuminate the mechanism by which CB2Rs can negatively modulate CB1R function.

In more recent years, three other novel receptor candidates, GPR18, GPR19 and GPR55, have been discovered, as well as non-CB1Rs and non-CB2Rs, but knowledge on these systems is incomplete and the discussion on whether or not they meet the criteria to qualify as receptors or channels is ongoing [Mackie and Stella, 2006; Pertwee et al. 2010;Pamplona and Takahashi, 2012]. It is generally established that some endocannabinoids, d-9-THC and several synthetic CB1R/CB2R agonists and antagonists can also interact with a number of non-CB1, non-CB2 GPCRs, ligand-gated ion channels and nuclear receptors (see the recent review by Pertwee and colleagues [Pertwee et al. 2010]). In conclusion, the biochemical mechanisms of this system are far more complex and the discussion on whether any known mammalian channel or non-CB1R/CB2R should be classified as a novel cannabinoid ‘CB3’ receptor or channel is ongoing.

The involvement of the particular neural regions and the neurotransmitter systems here is significant due to the fact that the very same brain areas and neurotransmitter systems are also implicated in psychoses, particularly in schizophrenia [van Os and Kapur, 2009; Smieskova et al. 2010; Stone, 2011].

Functions of the endocannabinoid receptor system

Available evidence indicates that we do not yet have a complete understanding of the varied functions of the endocannabinoid system, which is widely distributed both in the brain and in the peripheral system and most glands and organs in the body. However, there has been a dramatic increase in research exploring this system during the last decade and it is considered to be one of the fastest growing fields in psychopharmacology, whilst the number of ‘classic’ neurotransmitter’ studies have either declined or remained the same [Pamplona and Takahashi, 2012]. Even though our knowledge on the role of the endocannabinoid system is still evolving, the available evidence indicates that this system has multiple regulatory roles in neuronal, vascular, metabolic, immune and reproductory systems. As mentioned previously, the on-demand regulatory role on other neurotransmitter systems clearly affect functions such as cognition, memory, motor movements and pain perception [Howlett et al. 2002].

Delta-9-tetrahydrocannabinol and cannabidiol

Natural compounds of the cannabis plant are also referred to as phytocannabinoids of which d-9-THC is the main psychoactive ingredient and has been widely researched both in animals and humans. It characteristically produces, in a dose-dependent manner, hypoactivity, hypothermia, spatial and verbal short-term memory impairment [Hayakawa et al. 2007]. However, the second major compound, CBD, does not affect locomotor activity, body temperature or memory on its own. However, higher doses of CBD can potentiate the lower doses of d-9-THC by enhancing the level of CB1R expression in the hippocampus and hypothalamus. The authors suggest that CBD potentiates the pharmacological effects of d-9-THC via a CB1R-dependent mechanism [Hayakawa et al. 2007].

The available research indicates that the main two compounds, d-9-THC and CBD, whilst having similar effects in certain domains, also have almost opposite effects to one another in other aspects [Carlini et al. 1974;Borgwardt et al. 2008; Fusar-Poli et al. 2009; Morrison et al. 2009;Bhattacharyya et al. 2009b; Winton-Brown et al. 2011]. Table 1summarizes the varying effects of these two compounds.

Table 1.

Effects of tetrahydrocannabinol and cannabidiol, adapted and updated fromRusso and Guy [2006].

In fact the different and opposing effects of the main two compounds of the plant were noticed in some early studies. In a double-blind study with 40 healthy volunteers, Karniol and colleagues orally administered d-9-THC and CBD and the mixtures of the two together, whilst pulse rate, time production tasks and psychological reactions were measured [Karniol et al. 1974]. Whilst d-9-THC alone increased pulse rate, disturbed time tasks and induced strong psychological reactions in the subjects, CBD alone provoked no such effects. However, CBD was efficient in blocking most of the effects of d-9-THC when both drugs were given together. CBD also decreased the anxiety component of d-9-THC effects in such a way that the subjects reported more pleasurable effects.

Most recently there have been a number of drug challenge studies with sound methodologies examining the effects of both of these compounds. Our group carried out a number of double-blind, pseudo-randomized studies on healthy volunteers who had previous minimal exposure to cannabis. All participants were administered 10 mg of d-9-THC, 600 mg of CBD and placebo (flour) in three different functional magnetic resonance imaging sessions while performing a response inhibition task, a verbal memory task, an emotional task (viewing fearful faces) and an auditory and visual sensory processing task. The overall concluding results showed that d-9-THC and CBD had different behavioural effects and also, at times, opposing brain activation in various regions [Borgwardt et al. 2008; Fusar-Poli et al. 2009; Bhattacharyya et al. 2009b; Winton-Brown et al. 2011]. D-9-THC caused transient psychotic symptoms and increased the levels of anxiety, intoxication and sedation, whilst CBD had no significant effect on behaviour or these parameters.

In relation to the imaging data, during the response inhibition task, relative to placebo, d-9-THC attenuated the engagement of brain regions that normally mediate response inhibition, whilst CBD modulated activity in regions not implicated with this task [Borgwardt et al. 2008]. During the verbal learning and retrieval of word pair tasks, d-9-THC modulated activity in mediotemporal and ventrostriatal regions, whilst CBD had no such effect [Bhattacharyya et al. 2009b]. During an emotional processing task d-9-THC and CBD had clearly distinct effects on the neural, electrodermal and symptomatic response to fearful faces [Fusar-Poli et al. 2009]. Our results suggest that the effects of CBD on activation in limbic and paralimbic regions may contribute to its ability to reduce autonomic arousal and subjective anxiety, whereas the anxiogenic effects of d-9-THC may be related to effects in other brain regions. During the auditory task, again these two compounds had opposite effects in the superior temporal cortex when subjects listened to speech and in the occipital cortex during visual processing [Winton-Brown et al. 2011].

Our group also assessed whether pretreatment with CBD could prevent the acute psychotic symptoms induced by d-9-THC when six healthy volunteers were administered d-9-THC intravenously on two occasions, after placebo or CBD pretreatment [Bhattacharyya et al. 2010]. We found that pretreatment with CBD prevented the transient psychotic symptoms induced by d-9-THC.

Both animal and human studies indicate that CBD has anxiolytic properties. In fact in a recent double-blind study carried out on patients with generalized social anxiety disorder, it was found that relative to placebo, CBD significantly reduced subjective anxiety and its effect was related to its activity on limbic and paralimbic areas as shown by single photon emission computed tomography [Crippa et al. 2011].

CBD has also been proposed to have antipsychotic effects and is considered a potential antipsychotic medicine, particularly due its relatively low side-effect profile [Zuardi et al. 1995]. Furthermore, it is also being developed as a possible ‘medicine’ for various other conditions, such as inflammation, diabetes, cancer and neurodegenerative diseases [Izzo et al. 2009].

CBD is not the only compound which shows different effects to its main ingredient d-9-THC, a partial CB1R agonist. Another interesting compound of the plant, d-9-tetrahydrocannabivarin (d-9-THCV), a novel CB1R antagonist, also exerts potentially useful actions in the treatment of epilepsy and obesity [Pertwee, 2008; Izzo et al. 2009]. A review of this compound, along with d-9-THC and CBD by Pertwee suggests that plant extractions of d–9-THCV produces its antiobesity effects more by increasing energy expenditure than by reducing food intake [Pertwee, 2008]. The author also points out that a medicine such as d-9-THCV, by simultaneously blocking CB1Rs and activating CB2Rs, may have potential for the management of disorders such as chronic liver disease and obesity, particularly when these are associated with inflammation.

Intersubject variation in response to the psychotogenic effects of cannabis

About 18.5% of people in the UK use cannabis regularly [Atha, 2005]. This is important as the strong THC variants of cannabis use have been increasing steeply, as have concerns on cannabis-related health risks, particularly for young people [Hall and Degenhardt, 2007; Potter et al. 2008; EMCDDA, 2011]. Recent epidemiological studies point towards a link between the use of cannabis and the development of a psychotic illness [Zammit et al. 2002; van Os et al. 2002; Arseneault et al. 2002;Henquet et al. 2005]. Further evidence comes from a systematic review of longitudinal and population-based studies which show that cannabis use significantly increases the risk of development of a psychotic illness in a dose-dependent manner [Moore et al. 2007].

However, only a small minority develop a full-blown psychotic illness in the form of schizophrenia or bipolar disorder, whilst a larger group, ranging from 15% to 50%, experience transient psychotic symptoms of brief duration, from a couple of hours to up to a week, and usually recover without requiring any intervention [Thomas, 1996; Green et al. 2003; D’Souza et al. 2004, 2009; Morrison et al. 2009]. Indeed drug challenge studies with d-9-THC on healthy volunteers have shown a broad range of transient symptoms, behaviours and cognitive deficits ranging from anxiety to psychosis to transient memory disturbance [D’Souza et al. 2004; Curran et al. 2002; Morrison et al. 2009]. The clinical picture of transient psychosis can be indistinguishable from a frank acute psychosis with delusions and hallucinations, except for its short duration.

Evidently there is considerable variation in the effects of cannabis on individuals. The biological basis of this variable sensitivity is yet unclear. There have been a number of studies exploring which groups are more vulnerable to developing a psychotic outcome as a result of cannabis use [van Os et al. 2002; Henquet et al. 2004]. Findings so far indicate that the effect of cannabis use is much stronger in those with any predisposition for psychosis at baseline than in those without [Henquet et al. 2005]. Indeed, individuals with a predisposition to psychosis indicated by a positive family history of psychosis have been found to be particularly sensitive to the effects of cannabis [McGuire et al. 1995]. Another indicator for a higher psychosis risk is the presence of subclinical psychotic features and again such individuals have been affected by a higher risk of developing a psychotic illness [Henquet et al. 2004]. Furthermore those who are at ultra high risk for psychosis have been reported to be more sensitive to the psychotogenic effects of cannabis compared with users in the general population [Peters et al. 2009].

Because of the reported links between the schizotypal personality and schizophrenia, this type of personality disorder has come under scrutiny in examining the role of cannabis in producing psychotic symptoms. Indeed, it has been shown that people scoring high in schizotypy who use cannabis are more likely to have psychosis-like experiences at the time of use, together with unpleasant side effects [Barkus et al. 2006]. This study has been replicated and it has been confirmed that those with schizotypal personality disorder carry a higher risk of experiencing psychotic symptoms with cannabis use [Stirling et al. 2008]. Most recently, another study has provided further support for a strong association between early cannabis use and the development of schizophrenia spectrum disorder symptoms [Anglin et al. 2012].

The reported vulnerability factors mentioned here imply a strong genetic predisposition and there have been a number of studies looking particularly to specific genes which have been implicated in psychoses. The first such study was carried out by Caspi and colleagues [Caspi et al. 2005]. In this longitudinal study, a specific susceptibility gene which has been linked to schizophrenia and bipolar disorder, catechol-O-methyltransferase (COMT), was examined in a representative birth cohort followed to adulthood. The study found that carriers of the COMT valine158 allele were most likely to exhibit psychotic symptoms and to develop schizophreniform disorder if they used cannabis before the age of 15. However, the number of people carrying this allele was small in this study. Using a case-only design of 493 people with schizophrenia, Zammit and colleagues re-examined this association but their findings did not support the different effects of cannabis use on schizophrenia according to variation in COMT [Zammit et al. 2007]. Zammit’s group also looked for evidence of an interaction between cannabis use and COMT genotype by restricting the analysis to participants who claimed to have first used cannabis by the same cutoff period as the Caspi group, but failed to find evidence supporting the link.

More recently, van Winkel and colleagues looked at the effects of recent cannabis use whilst examining 152 single nucleotide polymorphisms in 42 candidate genes in 801 patients with psychosis and their 740 unaffected siblings [van Winkel et al. 2011]. The authors found that genetic variation in serine-threonine protein kinase (AKT1) may mediate both short- and long-term effects on psychosis expression associated with cannabis use. The authors suggest that the likely mechanism could be cannabinoid-regulated AKT1/glycogen synthase kinase 3 signalling downstream of the dopamine D2 receptor. Indeed, CB1R agonists have been shown to induce AKT1 phosphorylation, whilst the antagonists of this receptor have inhibited AKT1 signalling pathways [Molina-Holgado et al. 2002]. Further support for the possible involvement of the AKT1 gene comes from our study with healthy volunteers. This study found that, during the encoding and recall conditions of the verbal memory task, the induction of psychotic symptoms by d-9-THC was correlated with the attenuated striatal and midbrain activation only in those who were G homozygotes of AKT1 and carriers of the 9-repeat allele dopamine transporter (DAT1) [Bhattacharyya et al. 2012] (Table 2).

Table 2.

Proposed factors determining sensitivity to psychosis in cannabis users.^*

Apart from schizotypal personality, the vulnerability factors to the psychotogenic effects of cannabis require replication. It is clear that further work needs to be carried out to explore the biological mechanisms which determine the vulnerability towards a psychotic outcome.

Thanks to Ethan Russo and Geoffrey W. Guy for providing the inspiration for Table 1. Also thanks to Dr Sanem Atakan for her help with the editing of the first draft.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The author declare no conflicts of interest in preparing this article.

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