Depression-like phenotype following chronic CB1 receptor antagonism.
Rimonabant was the first clinically marketed cannabinoid (CB)(1) receptor antagonist developed to treat obesity. Unfortunately, CB(1) receptor antagonism produced adverse psychiatric events in patients. To determine whether this occurs pre-clinically, we investigated the effects of rimonabant in rodent models of mood disorders. Chronic treatment with rimonabant increased immobility time in the rat forced swim test and reduced the consumption of sucrose-sweetened water in an assay postulated to model anhedonia. These responses were similar to the effects elicited by chronic mild stress in these behavioral models, which, taken together, are indicative of a depression-like phenotype. Additionally, chronic treatment with rimonabant produced decreases in frontal cortex serotonin levels, marked reductions in hippocampal cell proliferation, survival, and BDNF levels, and elevations in the concentrations of pro-inflammatory cytokines including interferon gamma and TNF alpha. These preclinical findings mimic clinical reports and implicate possible mechanisms responsible for the unfavorable psychiatric events reported following chronic rimonabant use.
Beyer
Chad E
CE
Pfizer Global Research and Development, Princeton, NJ 08543, USA. chad.beyer@lohocla.com <chad.beyer@lohocla.com>
Dwyer
Jason M
JM
Piesla
Michael J
MJ
Platt
Brian J
BJ
Shen
Ru
R
Rahman
Zia
Z
Chan
Karen
K
Manners
Melissa T
MT
Samad
Tarek A
TA
Kennedy
Jeffrey D
JD
Bingham
Brendan
B
Whiteside
Garth T
GT
D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry / Q000379:methods; D005518:Food Preferences / Q000187:drug effects; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D017551:Microdialysis / Q000379:methods; D010641:Phenotype; D010880:Piperidines / Q000009:adverse effects*; D011720:Pyrazoles / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D013315:Stress, Psychological / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D013550:Swimming / Q000523:psychology
D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013549:Sweetening Agents; D013395:Sucrose; D000077285:Rimonabant