Downregulation of Endocannabinoid Signaling in the Hippocampus Following Chronic Unpredictable Stress

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 CB 1 receptor expression and significantly reduced the content of the endocannabinoid 2-arachidonylglycerol within the hippocampus. CB 1 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.

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

“…This suggests that simultaneous inhibition of FAAH and MAGL produces a synergistic increase in AEA and PEA levels in a tissuespecific manner. No change in the basal level of 2-AG was found in CUS mice compared with controls, although a decrease was found in the hippocampus (Figure 5c), as reported by Hill et al (2005), which, however, in our case, was not statistically significant (p ¼ 0.2). The basal 2-AG levels differed among the brain regions; the highest amounts were found in the hypothalamus (Figure 5d), midbrain (Figure 5e), and spinal cord (Figure 5f).…”

“…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).…”

Chronic Unpredictable Stress Induces a Cognitive Deficit and Anxiety-Like Behavior in Rats that is Prevented by Chronic Antidepressant Drug Treatment

“…In the present study, this may account in part for the inconsistent effects of CUS seen on stimulus reversal trials . It has been suggested that reversal of spatial learning in the Morris water maze may be impaired by CUS (Hill et al, 2005). However, by contrast with the effects on ED set shifting and morphologic changes seen in mPFC after repeated restraint stress, Liston et al (2006) reported no effects on reversal learning and no morphological changes in orbitofrontal cortex.…”

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…Reduction of AEA-CB 1 R signaling in the amygdala mediates the anxiogenic effects of corticotropin-releasing hormone [37], and CB 1 R activation is essential to negative feedback of the neuroendocrine stress response, and protects against the adverse effects of chronic stress [38,39]. Finally, chronic stress impairs eCB signaling in the hippocampus and amygdala, leading to anxiety [40,41], and people with PTSD show elevated CB 1 R availability and reduced peripheral AEA, suggestive of reduced eCB tone [42].…”