Species differences in cannabinoid receptor 2 and receptor responses to cocaine self-administration in mice and rats.
The discovery of functional cannabinoid receptors 2 (CB2Rs) in brain suggests a potential new therapeutic target for neurological and psychiatric disorders. However, recent findings in experimental animals appear controversial. Here we report that there are significant species differences in CB2R mRNA splicing and expression, protein sequences, and receptor responses to CB2R ligands in mice and rats. Systemic administration of JWH133, a highly selective CB2R agonist, significantly and dose-dependently inhibited intravenous cocaine self-administration under a fixed ratio (FR) schedule of reinforcement in mice, but not in rats. However, under a progressive ratio (PR) schedule of reinforcement, JWH133 significantly increased breakpoint for cocaine self-administration in rats, but decreased it in mice. To explore the possible reasons for these conflicting findings, we examined CB2R gene expression and receptor structure in the brain. We found novel rat-specific CB2C and CB2D mRNA isoforms in addition to CB2A and CB2B mRNA isoforms. In situ hybridization RNAscope assays found higher levels of CB2R mRNA in different brain regions and cell types in mice than in rats. By comparing CB2R-encoding regions, we observed a premature stop codon in the mouse CB2R gene that truncated 13 amino-acid residues including a functional autophosphorylation site in the intracellular C-terminus. These findings suggest that species differences in the splicing and expression of CB2R genes and receptor structures may in part explain the different effects of CB2R-selective ligands on cocaine self-administration in mice and rats.
Neuroropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
Hai-Ying
HY
Zhang
Neuroropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
Guo-Hua
GH
Bi
Neuroropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
Xia
X
Li
Neuroropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
Jie
J
Li
Center for Bioinformatics, College of Life Sciences, Peking University, Beijing, China.
Hong
H
Qu
Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking University, Beijing, China.
Shi-Jian
SJ
Zhang
Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine and Peking University, Beijing, China.
Chuan-Yun
CY
Li
Department of Biology, William Paterson University, Wayne, NJ, USA.
Emmanuel S
ES
Onaivi
Neuroropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
Eliot L
EL
Gardner
Neuroropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
Zheng-Xiong
ZX
Xi
Neurobiology of Relapse Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.
Qing-Rong
QR
Liu
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002186:Cannabinoids / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D051381:Rats; D020318:Rats, Long-Evans; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012055:Reinforcement Schedule; D012646:Self Administration; D013045:Species Specificity; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage
D002186:Cannabinoids; C571431:Cnr2 protein, mouse; D018765:Dopamine Uptake Inhibitors; D043885:Receptor, Cannabinoid, CB2; D013549:Sweetening Agents; D013395:Sucrose; D003042:Cocaine; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC