Functional expression of brain neuronal CB2 cannabinoid receptors are involved in the effects of drugs of abuse and in depression.
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.
Onaivi
Emmanuel S
ES
Department of Biology, William Paterson University, Wayne, New Jersey, USA. OnaiviE@wpunj.edu
Ishiguro
Hiroki
H
Gong
Jian-Ping
JP
Patel
Sejal
S
Meozzi
Paul A
PA
Myers
Lester
L
Perchuk
Alex
A
Mora
Zoila
Z
Tagliaferro
Patricia A
PA
Gardner
Eileen
E
Brusco
Alicia
A
Akinshola
B Emmanuel
BE
Liu
Qing-Rong
QR
Chirwa
Sanika S
SS
Hope
Bruce
B
Lujilde
Javier
J
Inada
Toshiya
T
Iwasaki
Shinya
S
Macharia
David
D
Teasenfitz
Lindsey
L
Arinami
Tadao
T
Uhl
George R
GR
D000818:Animals; D044466:Asian People / Q000235:genetics; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism; D003863:Depression / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism; D019966:Substance-Related Disorders / Q000235:genetics*
D016376:Oligonucleotides, Antisense; D043885:Receptor, Cannabinoid, CB2