Abstract
Deficits in cognitive functioning and flexibility are seen following both chronic stress and modulation of endogenous cannabinoid (eCB) signaling. Here, we investigated whether alterations in eCB signaling might contribute to the cognitive impairments induced by chronic stress. Chronic stress impaired reversal learning and induced perseveratory behavior in the Morris water maze without significant effect on task acquisition. These cognitive impairments were reversed by exogenous cannabinoid administration, suggesting deficient eCB signaling underlies these phenomena. In line with this hypothesis, chronic stress downregulated CB1 receptor expression and significantly reduced the content of the endocannabinoid 2-arachidonylglycerol within the hippocampus. CB1 receptor density and 2-arachidonylglycerol content were unaffected in the limbic forebrain. These data suggest that stress-induced downregulation of hippocampal eCB signaling contributes to problems in behavioral flexibility and could play a role in the development of perseveratory and ruminatory behaviors in stress-related neuropsychiatric disorders.
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Acknowledgements
This research was supported by NIH Grant R01-DA016967 and an Independent Investigator Award from NARSAD to CJH; a Natural Sciences and Engineering Research Council (NSERC) grant to BBG; an NSERC postgraduate scholarship and a Michael Smith Foundation for Health Research (MSFHR) Research Training Award to MNH; an NIH-NRSA grant (F30 DA15575) to SP; an NIH-NRSA grant (F32 DA16510) to DJR. We like to thank Maric Tse, Indy Gill, Eda Karacabeyli and Wayne Yu for their technical assistance.
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Hill, M., Patel, S., Carrier, E. et al. Downregulation of Endocannabinoid Signaling in the Hippocampus Following Chronic Unpredictable Stress. Neuropsychopharmacol 30, 508–515 (2005). https://doi.org/10.1038/sj.npp.1300601
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DOI: https://doi.org/10.1038/sj.npp.1300601
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