Depression-like phenotype following chronic CB1 receptor antagonism
Rimonabant was the first clinically marketed cannabinoid (CB)1 receptor antagonist developed to treat obesity. Unfortunately, CB1 receptor antagonism produced adverse psychiatric events in patients. To determine whether this occurs pre-clinically, we investigated the effects of rimonabant in rodent...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2010-08-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996110000926 |
| _version_ | 1818417560871239680 |
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| author | Chad E. Beyer Jason M. Dwyer Michael J. Piesla Brian J. Platt Ru Shen Zia Rahman Karen Chan Melissa T. Manners Tarek A. Samad Jeffrey D. Kennedy Brendan Bingham Garth T. Whiteside |
| author_facet | Chad E. Beyer Jason M. Dwyer Michael J. Piesla Brian J. Platt Ru Shen Zia Rahman Karen Chan Melissa T. Manners Tarek A. Samad Jeffrey D. Kennedy Brendan Bingham Garth T. Whiteside |
| author_sort | Chad E. Beyer |
| collection | DOAJ |
| description | Rimonabant was the first clinically marketed cannabinoid (CB)1 receptor antagonist developed to treat obesity. Unfortunately, CB1 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. |
| first_indexed | 2024-12-14T12:08:44Z |
| format | Article |
| id | doaj.art-076a332ba28d4a31822f0239f65decee |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-14T12:08:44Z |
| publishDate | 2010-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-076a332ba28d4a31822f0239f65decee2022-12-21T23:01:48ZengElsevierNeurobiology of Disease1095-953X2010-08-01392148155Depression-like phenotype following chronic CB1 receptor antagonismChad E. Beyer0Jason M. Dwyer1Michael J. Piesla2Brian J. Platt3Ru Shen4Zia Rahman5Karen Chan6Melissa T. Manners7Tarek A. Samad8Jeffrey D. Kennedy9Brendan Bingham10Garth T. Whiteside11Corresponding author. Pfizer Global Research and Development, CN 8000, Princeton, NJ 08543-8000, USA. Fax: +1 720 859 6110.; Pfizer Global Research and Development, Princeton, NJ 08543, USAPfizer Global Research and Development, Princeton, NJ 08543, USAPfizer Global Research and Development, Princeton, NJ 08543, USAPfizer Global Research and Development, Princeton, NJ 08543, USAPfizer Global Research and Development, Princeton, NJ 08543, USAPfizer Global Research and Development, Princeton, NJ 08543, USAPfizer Global Research and Development, Princeton, NJ 08543, USAPfizer Global Research and Development, Princeton, NJ 08543, USAPfizer Global Research and Development, Princeton, NJ 08543, USAPfizer Global Research and Development, Princeton, NJ 08543, USAPfizer Global Research and Development, Princeton, NJ 08543, USAPfizer Global Research and Development, Princeton, NJ 08543, USARimonabant was the first clinically marketed cannabinoid (CB)1 receptor antagonist developed to treat obesity. Unfortunately, CB1 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.http://www.sciencedirect.com/science/article/pii/S0969996110000926CannabinoidsRimonabantMood disordersChronic mild stressNeurogenesisCytokines |
| spellingShingle | Chad E. Beyer Jason M. Dwyer Michael J. Piesla Brian J. Platt Ru Shen Zia Rahman Karen Chan Melissa T. Manners Tarek A. Samad Jeffrey D. Kennedy Brendan Bingham Garth T. Whiteside Depression-like phenotype following chronic CB1 receptor antagonism Neurobiology of Disease Cannabinoids Rimonabant Mood disorders Chronic mild stress Neurogenesis Cytokines |
| title | Depression-like phenotype following chronic CB1 receptor antagonism |
| title_full | Depression-like phenotype following chronic CB1 receptor antagonism |
| title_fullStr | Depression-like phenotype following chronic CB1 receptor antagonism |
| title_full_unstemmed | Depression-like phenotype following chronic CB1 receptor antagonism |
| title_short | Depression-like phenotype following chronic CB1 receptor antagonism |
| title_sort | depression like phenotype following chronic cb1 receptor antagonism |
| topic | Cannabinoids Rimonabant Mood disorders Chronic mild stress Neurogenesis Cytokines |
| url | http://www.sciencedirect.com/science/article/pii/S0969996110000926 |
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