Cited by 258Cannabis and Cannabinoid ResearchNeurotransmitter Receptor Influence on BehaviorNeuropeptides and Animal Physiology

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

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Onaivi, Emmanuel S., Ishiguro, Hiroki, Gong, Jian-Ping, Patel, Sejal, Meozzi, Paul A., Myers, Lester, Perchuk, Alex, Mora, Zoila, Tagliaferro, Patricia A., Gardner, Eileen, Brusco, Alicia, Akinshola, B. Emmanuel, Hope, Bruce, Lujilde, Javier, Inada, Toshiya, Iwasaki, Shinya, Macharia, David, Teasenfitz, Lindsey, Arinami, Tadao, Uhl, George R.·2008·PLoS ONE

DOI 10.1371/journal.pone.0001640PMC PMC2241668

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Abstract

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 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/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.

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Authors: Onaivi, E. S., Ishiguro, H., Gong, J.-P., Patel, S., Meozzi, P. A., Myers, L., Perchuk, A., Mora, Z., Tagliaferro, P. A., Gardner, E., Brusco, A., Akinshola, B. E., Hope, B., Lujilde, J., Inada, T., Iwasaki, S., Macharia, D., Teasenfitz, L., Arinami, T., & Uhl, G. R.
Affiliations: William Paterson University (US)
National Institutes of Health (US)
Universidad de Buenos Aires (AR)
Howard University (US)
Teikyo University Chiba Medical Center (JP)
Corresponding author: Onaivi, Emmanuel S.
ORCID: Onaivi, Emmanuel S.
Ishiguro, Hiroki
Brusco, Alicia
Hope, Bruce
Inada, Toshiya
Uhl, George R.
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2008-02-20
Volume: 3
Issue: 2
Pages: e1640
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0001640
PMC: PMC2241668
OpenAlex: W1980460968
Cited by: 257
References: 37
Citations by year: 2026: 3 · 2025: 7 · 2024: 11 · 2023: 15 · 2022: 13 · 2021: 14 · 2020: 12 · 2019: 16 · 2018: 16 · 2017: 22 · 2016: 15 · 2015: 14 · 2014: 13 · 2013: 18 · 2012: 18
FWCI: 11.67
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS ONE (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: William Paterson University of New Jersey
National Institute on Alcohol Abuse and Alcoholism
National Institute on Drug Abuse
Topics: Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords: CB2 receptor, depression, substance abuse, alcohol preference, cocaine, opiates, ethanol, stress, antisense oligonucleotides, subcellular localization, Japanese patients
MeSH terms: Animals, Brain Chemistry, Depressive Disorder, Gene Expression Regulation, Humans, Neurons, Polymorphism, Genetic, Substance-Related Disorders, Receptor, Cannabinoid, CB2, Mice

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

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