Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress.
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.
Hill
Matthew N
MN
Department of Psychology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
Patel
Sachin
S
Carrier
Erica J
EJ
Rademacher
David J
DJ
Ormerod
Brandi K
BK
Hillard
Cecilia J
CJ
Gorzalka
Boris B
BB
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002186:Cannabinoids / Q000494:pharmacology*; D003307:Copulation / Q000187:drug effects / Q000502:physiology; D063388:Endocannabinoids; D005260:Female; D006624:Hippocampus / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology; D012016:Reference Values; D015398:Signal Transduction / Q000502:physiology*; D013315:Stress, Psychological / Q000097:blood / Q000503:physiopathology*
D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1