A role for 2-arachidonoylglycerol and endocannabinoid signaling in the locomotor response to novelty induced by olfactory bulbectomy

Abstract

Bilateral olfactory bulbectomy (OBX) in rodents produces behavioral and neurochemical changes associated clinically with depression and schizophrenia. Most notably, OBX induces hyperlocomotion in response to the stress of exposure to a novel environment. We examined the role of the endocannabinoid system in regulating this locomotor response in OBX and sham-operated rats. In our study, OBX-induced hyperactivity was restricted to the first 3 min of the open field test, demonstrating the presence of novelty (0-3 min) and habituation (3-30 min) phases of the open field locomotor response. Levels of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide were decreased in the ventral striatum, a brain region deafferented by OBX, whereas cannabinoid receptor densities were unaltered. In sham-operated rats, 2-AG levels in the ventral striatum were negatively correlated with distance traveled during the novelty phase. Thus, low levels of 2-AG are reflected in a hyperactive open field response. This correlation was not observed in OBX rats. Conversely, 2-AG levels in endocannabinoid-compromised OBX rats correlated with distance traveled during the habituation phase. In OBX rats, pharmacological blockade of cannabinoid CB 1 receptors with either AM251 (1 mg kg −1 i.p.) or rimonabant (1 mg kg −1 i.p.) increased distance traveled during the habituation phase. Thus, blockade of endocannabinoid signaling impairs habituation of the hyperlocomotor response in OBX, but not sham-operated, rats. By contrast, in sham-operated rats, effects of CB 1 antagonism were restricted to the novelty phase. These findings suggest that dysregulation in the endocannabinoid system, and 2-AG in particular, is implicated in the hyperactive locomotor response induced by OBX. Our studies suggest that drugs that enhance 2-AG signaling, such as 2-AG degradation inhibitors, might be useful in human brain disorders modeled by OBX.

Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats

“…Chronic handling attenuates both anxiety and heightened emotion induced by social isolation and concomitantly elevates 2-AG accumulation in the prefrontal cortex (40). In line with these observations, 2-AG, but not AEA, levels in the ventral striatum negatively correlate with the hyperlocomotor response elicited by the stress of exposure to a novel open field (41). The relationship between novelty-induced locomotion and 2-AG is also abolished by subjecting rats to olfactory bulbectomy, which deafferents the ventral striatum, and produces both a hyperactive response to novelty stress and a dysregulated affective state (41).…”

“…In line with these observations, 2-AG, but not AEA, levels in the ventral striatum negatively correlate with the hyperlocomotor response elicited by the stress of exposure to a novel open field (41). The relationship between novelty-induced locomotion and 2-AG is also abolished by subjecting rats to olfactory bulbectomy, which deafferents the ventral striatum, and produces both a hyperactive response to novelty stress and a dysregulated affective state (41). These data collectively suggest a role for 2-AG in regulating responsiveness to environmental stressors.…”

Role of the Endocannabinoid System in Depression: from Preclinical to Clinical Evidence

“…Recent data have suggested that 2-AG could act in the brain modulating behavioural responses in stress-related conditions [173][174][175]. In this context the prototypical MAGL inhibitor JZL184, by inducing an 8-fold increase in 2-AG, but not AEA, brain content reversed the depressive-like behaviour via activation of both CB1 receptor and mTor signaling [176].…”

Plants vs. Cancer: A Review on Natural Phytochemicals in Preventing and Treating Cancers and Their Druggability

“…Another example of curcumin is that it shows low bioavailability in earlier studies. To improve that, nanotechnology, liposomes, micelles, various coating materials, and phospholipid complexes have been applied to increase its water solubility and to enhance its bioavailability [314]. Genistein has limited bioavailability in earlier studies.…”