ReviewThe endocannabinoid system and psychiatric disorders
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
References (128)
- et al.
Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress
Biol. Psychiatry
(2007) - et al.
Models of schizophrenia in humans and animals based on inhibition of NMDA receptors
Neurosci. Biobehav. Rev.
(2008) - et al.
Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-o-methyltransferase gene: longitudinal evidence of a gene X environment interaction
Biol. Psychiatry
(2005) - et al.
Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use
Neuroscience
(2001) - et al.
Auditory gating in rat hippocampus and medial prefrontal cortex: effect of the cannabinoid agonist WIN55, 212-2
Neuropharmacology
(2008) - et al.
Cannabinoid receptor 1 (CNR1) gene: impact on antidepressant treatment response and emotion processing in major depression
Eur. Neuropsychopharmacol.
(2008) - et al.
A neurotrophic model for stress-related mood disorders
Biol. Psychiatry
(2006) - et al.
Cannabinoid CB1 receptor antagonism markedly increases dopamine receptor-mediated stereotypies
Eur. J. Pharmacol.
(2007) - et al.
Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain
Neuroscience
(1997) - et al.
A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner
Mol. Cell. Neurosci.
(2008)