Endocannabinoid system and mood disorders: Priming a target for new therapies

Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, Catania, Italy. Electronic address: .
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 12/2012; 138(1). DOI: 10.1016/j.pharmthera.2012.12.002
Source: PubMed


The endocannabinoid system (ECS), comprising two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol [Δ(9)-THC]), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and degradation, has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiopathological conditions. In the brain activation of this system modulates the release of excitatory and inhibitory neurotransmitters and of cytokines from glial cells. As such, the ECS is strongly involved in neuropsychiatric disorders, particularly in affective disturbances such as anxiety and depression. It has been proposed that synthetic molecules that inhibit endocannabinoid degradation can exploit the selectivity of endocannabinoid action, thus activating cannabinoid receptors only in those tissues where there is perturbed endocannabinoid turnover due to the disorder, and avoiding the potential side effects of direct CB1 and CB2 activation. However, the realization that endocannabinoids, and AEA in particular, also act at other molecular targets, and that these mediators can be deactivated by redundant pathways, has recently led to question the efficacy of such approach, thus opening the way to new multi-target therapeutic strategies, and to the use of non-psychotropic cannabinoids, such as cannabidiol (CBD), which act via several parallel mechanisms, including indirect interactions with the ECS. The state of the art of the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in mood disorders is discussed in this review article.

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    • "Fear extinction is a measure of learned inhibition of conditioned fear that has proven valuable as a translational assay for studying novel treatments for stress-and traumarelated disorders (Bukalo et al, 2014; Milad and Quirk, 2012; Singewald et al, 2015). Gene deletion or pharmacological antagonism of CB1R profoundly impairs extinction , whereas augmenting eCBs, or amygdala anandamide specifically, facilitates extinction (Bowers and Ressler, 2015; Gunduz-Cinar et al, 2013b; Micale et al, 2013). In parallel to this work on eCBs, a number of recent studies have demonstrated that chronic treatment with fluoxetine, but not certain other SSRIs, such as citalopram (Burghardt and Bauer, 2013), facilitates extinction (Camp et al, 2012; Deschaux et al, 2011, 2013; Hartley et al, 2012; Karpova et al, 2012; Norcross et al, 2008; Popova et al, 2014; Riddle et al, 2013; Spennato et al, 2008). "
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    ABSTRACT: Pharmacologically elevating brain endocannabinoids (eCBs) shares anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's pro-extinction effects, we integrated biochemical, electrophysiological, pharmacological and behavioral techniques, employing the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase (FAAH). Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1Rs. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the pro-extinction effects of a major pharmacotherapy for Trauma- and Stressor-related Disorders and Anxiety Disorders.Neuropsychopharmacology accepted article preview online, 30 October 2015. doi:10.1038/npp.2015.318.
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    • "Cannabinoids are often reported to have both anxiolytic and anxiogenic properties (Campolongo et al. 2011; Haring et al. 2012; Hill & Gorzalka 2009; Marco & Laviola 2012). While cannabis use is generally associated with stress relief and mood elevation, in some cases, it produces dysphoric responses that include panic or heightened anxiety (Hall & Solowij 1998; Lafenetre et al. 2007; Mechoulam & Parker 2012; Micale et al. 2013). These biphasic effects are consistent with rodent studies demonstrating dose-dependent effects of CB 1 R agonists, such as THC, on anxiety behavior; "
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    • "We obtained the following findings: (i) the endocannabinoid uptake inhibitor AM404, but not VDM11, turned the sustained freezing response into a decaying freezing response; (ii) blocking the degradation of AEA by URB597 also decreased the expression of conditioned fear; and (iii) blocking the degradation of 2-AG by JZL184, in contrast, promoted the expression of conditioned fear, similarly to CP55,940. The fear-alleviating effects of URB597 are in accordance with the literature (Busquets-Garcia et al. 2011; for reviews, see Riebe et al. 2012; Micale et al. 2013). In the present study, the effects of URB597 seem to outlast the acute consequences on fear relief, since we observed a lasting decrease in freezing also at d10, i.e., without additional URB597 treatment. "
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