Impairments in Endocannabinoid Signaling and Depressive Illness

ArticleinJAMA The Journal of the American Medical Association 301(11):1165-6 · April 2009with3 Reads
DOI: 10.1001/jama.2009.369 · Source: PubMed
    • "The potent ability of CB 1 receptor antagonists to suppress cue-induced drug relapse (Section 1.2) also indicates potentially powerful cannabinoid-based addiction treatments. However, CB 1 receptor antagonists, while effective, are associated with significant negative side effects in humans, such as depression and suicidal tendencies (Hill and Gorzalka, 2009). Alternatively, because eCB mobilization occurs only in response to heightened activity, disrupting endogenous activity (e.g., by blocking enzymatic degradation) may more selectively target those synapses that are active during a specific event, such as re-exposure to drug cues (Oleson et al., 2014; Loewinger et al., 2013; Katona and Freund, 2008). "
    [Show abstract] [Hide abstract] ABSTRACT: Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana’s illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana’s psychoactive and reinforcing properties. CB1 receptors are also part of the brain endocannabinoid (eCB) system and support numerous forms of learning and memory, including the conditioned reinforcing properties of cues predicting reward or punishment. This is accomplished via eCB-dependent alterations in mesolimbic dopamine function, which plays an obligatory role in reward learning and motivation. Presynaptic CB1 receptors control midbrain dopamine neuron activity and thereby shape phasic dopamine release in target regions, particularly the nucleus accumbens (NAc). By also regulating synaptic input to the NAc, CB1 receptors modulate NAc output onto downstream neurons of the basal ganglia motor circuit, and thereby support goal-directed behaviors. Abused drugs promote short- and long-term adaptations in eCB-regulation of mesolimbic dopamine function, and thereby hijack neural systems related to the pursuit of rewards to promote drug abuse. By pharmacologically targeting the CB1 receptors, marijuana has preferential access to this neuronal system and can potently alter eCB-dependent processing of reward-related stimuli. As marijuana legalization progresses, greater access to this drug should increase the utility of marijuana as a research tool to better understand the eCB system, which has the potential to advance cannabinoid-based treatments for drug addiction.This article is part of a Special Issue entitled SI:Addiction circuits.This article is part of a Special Issue entitled SI:Addiction circuits.
    Full-text · Article · Nov 2014
    • "During recent decades, the overall risk of suffering from depression has increased and the age of onset has decreased. Recently, a growing body of evidence from pharmacological and genetic studies has suggested that the endocannabinoid system (ECS) is involved in the regulation of mood234 and anxiety disorders [5,6]. The endocannabinoids act through cannabinoid receptors, CB 1 and CB 2 , which couple to the Gα i/o class of G-proteins and have presynaptic or postsynaptic distribution in the brain789. "
    [Show abstract] [Hide abstract] 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
    • "Indeed, the ratio of Bcl-2/ Bax is used as a neuroprotection index, as well as an evaluation for the neuroprotective effect of antidepressants (Wang et al., 2011cWang et al., , 2013). Despised the role of the endocannabinoid system in mood regulation (Hill and Gorzalka, 2009; Lutz, 2009), CB1 receptor has been reported to participate in the mechanisms of depression (Manzanares et al., 2004), and alterations of endocannabinoid signaling might occur in the hippocampus in depression. Several studies investigated the role of the endocannabinoid system in hippocampal and they found that activation of CB1 receptor seemed to increase the expression of BDNF and the prominently decreased hippocampal neurogenesis was found in CB1-knockout mice (Dubreucq et al., 2010), and the involvement of CB1 receptor in hippocampal neuroprotection and neurogenesis has been documented (Haghani et al., 2012; Wolf et al., 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) to treat depression has been thoroughly investigated in recent years. However, the underlying mechanisms are not fully understood. In this study, a chronic unpredictable mild stress (CUMS) paradigm was applied to male Sprague Dawley rats. Then rTMS was performed for 7 consecutive days, and the anti-depressive effects were evaluated by the sucrose preference test (SPT), the forced swimming test (FST), and the open-field test (OFT). Hippocampal cannabinoid type I receptor (CB1) expression was measured, and the expression levels of brain-derived neurotrophic factor (BDNF), Bcl-2, and Bax and the number of bromodeoxyuridine (BrdU)-positive cells were also investigated. These parameters were also observed after the selective CB1 receptor antagonist AM251 was used as a blocking agent. The results showed that CUMS induced a significant decrease in sucrose preference, a significant increase in immobility time in the FST, and a significantly decreased horizontal distance in the OFT. In addition, reduced hippocampal CB1 receptor, BDNF, and Bcl-2/Bax protein expression levels in CUMS rats, as well as decreased cell proliferation were also observed in the dentate gyrus. Meanwhile, rTMS treatment up-regulated cell proliferation; elevated CB1 receptor, BDNF, and Bcl-2/Bax expression levels in the hippocampus; and ameliorated depressive-like behaviors. All of these beneficial effects were abolished by AM251. These results indicate that rTMS increases BDNF production and hippocampal cell proliferation to protect against CUMS-induced changes through its effect on CB1 receptors.
    Article · Jan 2014
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