Introduction

The term “psychosis” is very broad and denotes a variety of mental disorders. Schizophrenia is a particular kind of psychosis and is associated with a myriad of signs including positive symptoms such as delusion and hallucination, negative symptoms such as lack of motivation and social withdrawal, and cognitive symptoms such as reduced attention and altered speech [1, 2]. This disorder, which typically emerges during late adolescence and early adulthood, affects approximately 1 % of the population worldwide [3]. One of the most enduring model of schizophrenia is the dopamine hypothesis, which speculates that the psychotic symptoms of this disorder are due to a hyperfunction of dopaminergic signaling in the brain [4, 5]. Evidence supporting this hypothesis comes from the observation that compounds that are effective in treating schizophrenia were found to block dopamine D2 receptors [4, 6]. Nowadays, antipsychotics are classified into two classes: the typical and atypical antipsychotics. In contrast to typical antipsychotics, atypical antipsychotics bind loosely to D2 receptors and exert part of their therapeutic effects by binding to serotonin type 2A (5-HT2A) receptors [7]. Although being considered the cornerstone in the management of schizophrenia, antipsychotic drugs are associated with serious limitations. Treatment with typical antipsychotics is often linked with extrapyramidal side effects such as tremors, spasticity, and tardive dyskinesia [8, 9], whereas atypical antipsychotics are associated with severe complications such as sedation and weight gain [10, 11]. As a result, approximately half of patients with schizophrenia are non-adherent to antipsychotic medication and are more likely to experience symptoms of psychosis upon drug discontinuation [12, 13].

Until recently, the predominant focus of research concerning the biological basis of schizophrenia has been primarily centered on the role of neurotransmitters including dopamine, serotonin, norepinephrine, glutamate, and glutamate and γ-aminobutyric acid (GABA). However, given the limited efficiency of drugs that act on these neurotransmitters, researchers are now investigating the role of other neurotransmitter substrates in the pathophysiology of schizophrenia. One such substrate is the endocannabinoid system (ECS). The ECS is composed of cannabinoid receptors, endogenous cannabinoid ligands, and enzymes responsible for the biosynthesis and degradation of endocannabinoids [14]. This newly discovered system of neuromodulation participates in several physiological and behavioral processes such as pain [15], emotion [16], appetite [17], energy metabolism [18], mood [19], and memory [20]. Recent preclinical studies evaluating the levels of brain endocannabinoids in animal models of schizophrenia have suggested that the ECS could play a role in the pathophysiology of this disorder [21, 22]. Genetic and postmortem studies investigating the neurochemical changes in the brain of patients with schizophrenia provided additional evidence for the role of the ECS in psychotic and schizophrenia-like symptoms [1, 23]. However, despite the large amount of work devoted to this field of research, still more effort is needed to fully elucidate the role of the ECS in schizophrenia. More particularly, the mechanisms by which the ECS is associated with psychotic and schizophrenia-like symptoms remain to be determined in appropriate animal models.

The overarching goal of this review is to provide a better understanding of the contribution of the ECS in the pathophysiology of schizophrenia. This paper starts by describing some of the most recent studies investigating the link between cannabis use and psychosis and then provides an overview of evidences indicating a dysfunction of the ECS in schizophrenia. Finally, a closer look will be given at pharmacological tools that aimed at targeting the ECS for therapeutic purposes.

Cannabis Use and Psychosis : Towards a “Cannabinoid Hypothesis” of Schizophrenia

Cannabis is considered one of the most frequently used illicit drugs, and most consumers first experiment it during adolescence [24, 25]. Psychotic disorders such as schizophrenia are strongly associated with the regular consumption of cannabis, especially when consumed during adolescence and young adulthood [26]. Among consumers of cannabis, only individuals who are genetically vulnerable to its psychotomimetic effect will develop the symptoms of psychosis [27]. Adolescents are generally more affected by the long-term effects of cannabis because their brain is still in a phase of development and is therefore more vulnerable to environmental insults [24, 28].

Among all the chemical constituents of cannabis, delta- 9-tetrahydrocanabinol (THC) is by far the most studied and is responsible for the majority of the psychotropic effects of cannabis. THC exerts its action in the brain by binding to cannabinoid receptors type 1 (CB1) and type 2 (CB2) [29, 30]. Continuous exposure to THC has been shown to upregulate the ECS, leading to long-lasting neurobiological
changes in various regions of the brain [31]. By acting on cannabinoid receptors, THC also influences the release of neurotransmitters involved in the pathophysiology of schizophrenia, including dopamine and glutamate [32]. As a result, heavy consumption of cannabis most often has harmful effects on an individual’s health and can lead to the development of psychosis and schizophrenic-like symptoms [24, 33].

In the past decades, longitudinal studies investigating cannabis use in psychosis have prompted debates as to whether the ECS might be involved in the pathogenesis of schizophrenia. Even though the first observation between cannabis and schizophrenia was made almost 60 years ago [34], it was not until 1987 that the first longitudinal study provided empirical evidence of the increased risk of schizophrenia among cannabis users [35]. Since then, several other reports, which are summarized in Table 1, have shown similar risk and prevalence data. The results from these studies, along with other evidences from neuroimaging and postmortem analysis [46, 47], have led to the formulation of the Bcannabinoid hypothesis,^ which speculates that hyperactivity of the ECS may be associated with increased risk of developing symptoms of schizophrenia, mainly by increasing dopamine neurotransmission in the brain. In accordance with this hypothesis, several reports have observed high levels of cannabinoid receptors and endocannabinoid ligands in animal models of schizophrenia and psychotic patients. However, despite the large amount of research, the exact role of the ECS in schizophrenia has eluded the scientific community and remains to be characterized.

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Molecular neurobiology, 2017