Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: From mice to human subjects

Emmanuel S. Onaivi, Hiroki Ishiguro, Jian Ping Gong, Sejal Patel, Paul A. Meozzi, Lester Myers, Alex Perchuk, Zoila Mora, Patricia A. Tagliaferro, Eileen Gardner, Alicia Brusco, B. Emmanuel Akinshola, Bruce Hope, Javier Lujilde, Toshiya Inada, Shinya Iwasaki, David Macharia, Lindsey Teasenfitz, Tadao Arinami, George R. Uhl

Research output: Contribution to journalArticlepeer-review

187 Scopus citations


Background: Addiction 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 Findings: In 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 demostrate 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 naive mice and are modulated following exposure to stessors 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/Significance: Our 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.

Original languageEnglish (US)
Article numbere1640
JournalPLoS One
Issue number2
StatePublished - Feb 20 2008
Externally publishedYes

ASJC Scopus subject areas

  • General Agricultural and Biological Sciences
  • General Biochemistry, Genetics and Molecular Biology
  • General Medicine


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