Article

Downregulation of Endocannabinoid Signaling in the Hippocampus Following Chronic Unpredictable Stress

Department of Pharmacology and Toxicology , Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Neuropsychopharmacology (Impact Factor: 7.05). 04/2005; 30(3):508-15. DOI: 10.1038/sj.npp.1300601
Source: PubMed

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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Available from: Brandi K Ormerod, Jan 10, 2014
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    • "Inhibitors of eCB degradation have anxiolytic properties and are effective for the treatment of multiple types of pain. However, the mechanisms by which eCB signaling enhancing drugs modulate chronic pain associated with neurological diseases have remained largely unknown (Hill et al, 2005; Reich et al, 2009). Chronic unpredictable stress (CUS) is a common procedure to induce anxiety-and depression-like behaviors in rodents (Mineur et al, 2006). "

    Full-text · Dataset · Jan 2016
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    • "The effects of acute and repeated stress on 2-AG levels are also remarkably consistent between studies and laboratories. In most cases acute stress has little effect on 2-AG levels; however, repeated homotypic stress increases 2-AG levels in the amygdala and other limbic brain regions [17,84,86-88], while CUS has more variable effects [83], but often showing a decrease in hippocampal 2-AG levels [89]. Interestingly, chronic corticosterone treatment also increases amygdalar 2-AG levels [90]. "
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    • "The effects of the endocannabinoid system on executive functioning have been extensively studied in animal models. In vitro experiments have indicated a clear role of endocannabinoids on behavioral flexibility, whereby reduced levels of 2-AG in the hippocampus resulted in poor flexibility [25], [26]. In addition, some animal studies suggested that endocannabinoids have a negative impact on set-shifting and cognitive flexibility, and that the use of antagonists of CB1 receptors can improve such executive functions [27]. "
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