Functional expression of brain neuronal CB2 cannabinoid receptors are involved in the effects of drugs of abuse and in depression

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, Qing Rong Liu, Sanika S. Chirwa, Bruce Hope, Javier Lujilde, Toshiya Inada, Shinya Iwasaki, David Macharia, Lindsey TeasenfitzTadao Arinami, George R. Uhl

Research output: Chapter in Book/Report/Conference proceedingConference contribution

125 Scopus citations


Major depression and addiction are mental health problems associated with stressful events in life with high relapse and recurrence even after treatment. Many laboratories were not able to detect the presence of CB2 cannabinoid receptors (CB2-Rs) in healthy brains, but CB2-R expression has been demonstrated in rat microglial cells and other brain-associated cells during inflammation. Thus, neuronal expression of CB2-Rs has been ambiguous and controversial, and its role in depression and substance abuse is unknown. In this study we tested the hypothesis that genetic variants of the 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 after exposure to stressors and administration of abused drugs. Mice that developed an 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 antisense 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. Using electron microscopy we report the subcellular localization of CB2-Rs that are mainly on postsynaptic elements in rodent brain. Our data demonstrate the functional expression of CB2-Rs in the brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuroimmunocannabinoid activity.

Original languageEnglish (US)
Title of host publicationAnnals of the New York Academy of Sciences
Number of pages16
StatePublished - Oct 2008
Externally publishedYes

Publication series

NameAnnals of the New York Academy of Sciences
ISSN (Print)00778923
ISSN (Electronic)17496632


  • Anhedonia
  • Brain
  • Chronic mild stress
  • Depression
  • Drug abuse
  • Electron micrograph
  • Neuronal CB2 cannabinoid receptors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


Dive into the research topics of 'Functional expression of brain neuronal CB2 cannabinoid receptors are involved in the effects of drugs of abuse and in depression'. Together they form a unique fingerprint.

Cite this