Review
The endocannabinoid system and psychiatric disorders

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Abstract

The present review summarizes the latest information on the role and the pharmacological modulation of the endocannabinoid system in mood disorders and its potential implication in psychotic disorders such as schizophrenia.

Reduced functionality might be considered a predisposing factor for major depression, so boosting endocannabinoid tone might be a useful alternative therapeutic approach for depressive disorders. The picture regarding endocannabinoids and anxiety is more complicated since either too much or too little anandamide can lead to anxiety states. However, a small rise in its level in specific brain areas might be beneficial for the response to a stressful situation and therefore to tone down anxiety. This effect might be achieved with low doses of cannabinoid indirect agonists, such as blockers of the degradative pathway (i.e. FAAH) or re-uptake inhibitors.

Moreover several lines of experimental and clinical evidence point to a dysregulation of the endocannabinoid system in schizophrenia. The high anandamide levels found in schizophrenic patients, negatively correlated with psychotic symptoms, point to a protective role, whereas the role of 2-arachidonoyl glycerol is still unclear. There is a potential for pharmacological manipulation of the endocannabinoid system as a novel approach for treating schizophrenia, although experimental findings are still controversial, often with different effects depending on the drug, the dose, the species and the model used for simulating positive or negative symptoms. Besides all these limitations, SR141716A and cannabidiol show the most constant antipsychotic properties in dopamine- and glutamate-based models of schizophrenia, with profiles similar to an atypical antipsychotic drug.

Introduction

The endocannabinoid system is a recently discovered signaling system comprising the cannabinoid CB1 and CB2 receptors, their intrinsic lipid ligands, endocannabinoids (eCB) such as the N-arachidonoyl ethanolamide (anandamide, AEA) and the 2-arachidonoyl glycerol (2-AG), and associated proteins (transporters, biosynthetic and degradative enzymes).

The eCBs in the central nervous system are involved in numerous physiological functions and act on membrane receptors through paracrine and autocrine mechanisms. Dysregulation of the eCB system has been associated with various pathophysiological states, including psychiatric disorders. The high level of expression of CB1 receptors in brain areas involved in the regulation of cognition and mood functions (amygdala, cortex and hippocampus) implies that the eCB system is probably involved in emotional processing, mood and anxiety regulation and in the pathophysiology of depression. Recent data also suggest that changes in eCB signaling and the consequences on neuronal activity might be important in the etiology of schizophrenia and may help explain the impact of cannabis abuse in psychotic disorders.

The present review summarizes the latest breakthroughs on the eCB system's role and its pharmacological modulation in mood disorders and the potential implication in psychotic disorders such as schizophrenia.

Section snippets

The eCB system in depression

Cannabis sativa has long been known by humans for its mood-elevating and stress-reducing properties. However, the first comprehensive scientific paper openly discussing the idea that the endocannabinoid system might play a role in the neurobiology of depression is fairly recent, dating back only to 2005 (Hill and Gorzalka, 2005a). Since then the literature on this topic has accumulated providing evidence of dysregulation in endocannabinoid signaling as a molecular underpinning for mood

CB1 receptor

Schizophrenia may be associated with anomalies in the functions of the cannabinoid receptors and their attendant system of endogenous activators. These receptors are the pharmacological target of cannabis derived drugs that contain THC and convergent findings from epidemiological studies indicate that cannabis consumption constitutes a substantial environmental risk factor for schizophrenia, especially when exposure occurs during adolescence (Henquet et al., 2005, Moore et al., 2007). These

Mood disorders

Alterations in the eCB system appear to play a key role in mood disorders. Reduced functionality might be considered a predisposing factor for major depression, so boosting the eCB tone might be a useful alternative therapeutic approach for depressive disorder.

The picture regarding eCBs and anxiety is more complicated since either too much or too little AEA can lead to anxiety states. However, a small raise in its level in specific brain areas might be beneficial for the response to a stressful

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