Impairments in Endocannabinoid Signaling and Depressive Illness

Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Ave, New York, NY 10021, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 04/2009; 301(11):1165-6. DOI: 10.1001/jama.2009.369
Source: PubMed
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    • "Recently, a growing body of evidence from pharmacological and genetic studies has suggested that the endocannabinoid system (ECS) is involved in the regulation of mood [2] [3] [4] and anxiety disorders [5] [6]. "
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    ABSTRACT: Recent evidence suggests that the cannabinoid receptor subtype 2 (CB2) is implicated in anxiety and depression disorders, although few systematic studies in laboratory animals have been reported. The aim of the current experiments was to test the effects of the CB2 receptor potent-selective agonist β-caryophyllene (BCP) in animals subjected to models of anxiolytic- and antidepressant-like effects. Therefore effects of BCP (50mg/kg) on anxiety were assessed using the elevated plus maze (EPM), open field (OF), and marble burying test (MBT). However for depression, the novelty-suppressed feeding (NSF), tail suspension test (TST), and forced swim tests (FST) were used. Results indicated that adult mice receiving BCP showed amelioration of all the parameters observed in the EPM test. Also, BCP significantly increased the time spent in the center of the arena without altering the general motor activity in the OF test. This dose was also able to decrease the number of buried marbles and time spent digging in the MBT, suggesting an anti-compulsive-like effect. In addition, the systemic administration of BCP reduced immobility time in the TST and the FST. Finally, BCP treatment decreased feeding latency in the NSF test. Most importantly, pre-administration of the CB2 receptor antagonist AM630, fully abrogated the anxiolytic and the anti-depressant effects of BCP. Taken together, these preclinical results suggest that CB2 receptors may provide alternative therapeutic targets for the treatment of anxiety and depression. The possibility that BCP may ameliorate the symptoms of these mood disorders offers exciting prospects for future studies.
    Full-text · Article · Jun 2014 · Physiology & Behavior
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    • "Selective serotonin reuptake inhibitor (SSRI) treatment is known to cause alterations in CB1 receptor levels in the HC [45,46] and these alterations might be the consequences of the altered serotonergic tone. Activation of serotonin 2C (5-HT 2C) receptors increases endocannabinoid production in the postsynaptic HC and amygdala neurons via the downstream activation of diacylglycerol (DAG) lipase [45]. "
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    ABSTRACT: 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug known to impair cognitive functions on the long-run. Both hippocampal and frontal cortical regions have well established roles in behavior, memory formation and other cognitive tasks and damage of these regions is associated with altered behavior and cognitive functions, impairments frequently described in heavy MDMA users. The aim of this study was to examine the hippocampus, frontal cortex and dorsal raphe of Dark Agouti rats with gene expression arrays (Illumina RatRef bead arrays) looking for possible mechanisms and new candidates contributing to the effects of a single dose of MDMA (15 mg/kg) 3 weeks earlier. The number of differentially expressed genes in the hippocampus, frontal cortex and the dorsal raphe were 481, 155, and 15, respectively. Gene set enrichment analysis of the microarray data revealed reduced expression of 'memory' and 'cognition', 'dendrite development' and 'regulation of synaptic plasticity' gene sets in the hippocampus, parallel to the upregulation of the CB1 cannabinoid- and Epha4, Epha5, Epha6 ephrin receptors. Downregulated gene sets in the frontal cortex were related to protein synthesis, chromatin organization, transmembrane transport processes, while 'dendrite development', 'regulation of synaptic plasticity' and 'positive regulation of synapse assembly' gene sets were upregulated. Changes in the dorsal raphe region were mild and in most cases not significant. The present data raise the possibility of new synapse formation/synaptic reorganization in the frontal cortex three weeks after a single neurotoxic dose of MDMA. In contrast, a prolonged depression of new neurite formation in the hippocampus is suggested by the data, which underlines the particular vulnerability of this brain region after the drug treatment. Finally, our results also suggest the substantial contribution of CB1 receptor and endocannabinoid mediated pathways in the hippocampal impairments. Taken together the present study provides evidence for the participation of new molecular candidates in the long-term effects of MDMA.
    Full-text · Article · Dec 2013 · BMC Genomics
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    • "Clinical development of CB1 receptor antagonists was initially advanced as a putative mechanism to treat obesity, given that eCB signaling promotes feeding and weight gain, and that a blockade of eCB signaling in animals could mitigate the effects of diet-induced obesity. In humans, clinical studies have clearly demonstrated that blocking CB1 does provide some therapeutic benefit in promoting weight loss and alleviating metabolic abnormalities associated with obesity; however, the first CB1 receptor antagonist tested, rimonabant, developed specifically for this purpose, was ultimately removed from the market due to the development of anxiety and depressive symptoms in a significant proportion of individuals [101,102]. In fact, a meta-analysis of the four major clinical studies performed with rimonabant found that there was approximately a threefold increase in the emergence of anxiety symptoms in patients receiving rimonabant versus a placebo, and these studies were all performed on individuals who had no history of psychiatric illness [103]. "
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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.
    Full-text · Article · Oct 2013 · Biology of Mood and Anxiety Disorders
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