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


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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    ABSTRACT: Accumulating evidence over the past decade has highlighted an important role of the endocannabinoid (eCB) system in the regulation of stress and emotional behavior across divergent species, from rodents to humans. The general findings from this work indicate that the eCB system plays an important role in gating and buffering the stress response, dampening anxiety and regulating mood. Work in rodents has allowed researchers to determine the neural mechanisms mediating this relationship while work in human populations has demonstrated the possible importance of this system in stress-related psychiatric diseases, such as post-traumatic stress disorder, generalized anxiety and major depression. These stress-protective effects of eCB signaling appear to be primarily mediated by their actions within corticolimbic structures, particularly the amygdala and the prefrontal cortex. The aim of this review is to provide an up-to-date discussion of the current level of knowledge in this field, as well as address the current gaps in knowledge and specific areas of research that require attention.
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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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    ABSTRACT: Animal studies point to an implication of the endocannabinoid system on executive functions. In humans, several studies have suggested an association between acute or chronic use of exogenous cannabinoids (Δ9-tetrahydrocannabinol) and executive impairments. However, to date, no published reports establish the relationship between endocannabinoids, as biomarkers of the cannabinoid neurotransmission system, and executive functioning in humans. The aim of the present study was to explore the association between circulating levels of plasma endocannabinoids N-arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) and executive functions (decision making, response inhibition and cognitive flexibility) in healthy subjects. One hundred and fifty seven subjects were included and assessed with the Wisconsin Card Sorting Test; Stroop Color and Word Test; and Iowa Gambling Task. All participants were female, aged between 18 and 60 years and spoke Spanish as their first language. Results showed a negative correlation between 2-AG and cognitive flexibility performance (r = -.37; p<.05). A positive correlation was found between AEA concentrations and both cognitive flexibility (r = .59; p<.05) and decision making performance (r = .23; P<.05). There was no significant correlation between either 2-AG (r = -.17) or AEA (r = -.08) concentrations and inhibition response. These results show, in humans, a relevant modulation of the endocannabinoid system on prefrontal-dependent cognitive functioning. The present study might have significant implications for the underlying executive alterations described in some psychiatric disorders currently associated with endocannabinoids deregulation (namely drug abuse/dependence, depression, obesity and eating disorders). Understanding the neurobiology of their dysexecutive profile might certainly contribute to the development of new treatments and pharmacological approaches.
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