Brain Neuronal CB2 Cannabinoid Receptors in Drug Abuse and Depression: From Mice to Human Subjects

Abstract

BackgroundAddiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs) in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown.Methodology/Principal FindingsIn this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R) but not (H316Y) polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain.Conclusions/SignificanceOur data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity.

Endocannabinoid-mediated modulation of stress responses: Physiological and pathophysiological significance

“…In this context, it is also interesting to note that a number of recent studies have demonstrated a role for the CB 2 receptor, classically associated with the immune system, in anxiety-and depression-related behaviour. Thus, intracerebroventricular administration of antisense oligonucleotide sequence directed against CB 2 mRNA reduced anxiety-like behaviour in the mouse elevated plus-maze (Onaivi et al, 2008). Moreover, a high incidence of the Q63R polymorphism in the CB 2 receptor gene was found in Japanese subjects diagnosed with depression (Onaivi et al, 2008).…”

“…The CB 2 receptor is expressed in tissues and cells of the immune system (Munro et al, 1993;Parolaro, 1999). Its localization on glial cells (Cabral and Marciano-Cabral, 2005;Massi et al, 2008;Walter et al, 2003) means that it too may be capable of modulating central nervous system functioning and some recent evidence also suggests that CB 2 receptors may be expressed in neurones (Gong et al, 2006;Onaivi et al, 2008;Van Sickle et al, 2005). The above is a cursory introduction to a signalling system whose intriguing complexity has become more and more evident with the proliferation of research papers on this topic in recent years.…”

Role of CB2 Cannabinoid Receptors in the Rewarding, Reinforcing, and Physical Effects of Nicotine

“…The first results showed increased CB2r gene expression in the brain of mice after chronic treatment with heroin or cocaine and decreased CB2r gene expression in striatum and ventral midbrain of mice after chronic ethanol intake (Onaivi et al, 2008a). In fact, mice that developed alcohol preference presented reduced CB2r gene expression, and chronic treatment with JWH015, a CB2r agonist, enhanced alcohol consumption in stressed mice, whereas the administration of the CB2r antagonist AM630 reduced alcohol intake in stressed mice (Ishiguro et al, 2007).…”

No association between the functional cannabinoid receptor type 2 Q63R variants and inflammatory bowel disease in Turkish subjects

“…Previous studies have shown that the Q63R polymorphism of the CB2 gene is associated with alcoholism and depression in Japanese individuals (29,30). Moreover, this polymorphism may predispose to the development of childhood immune thrombocytopenic purpura in independent populations from Italy (31) and Egypt (32).…”