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de Bitencourt RM, Pamplona FA, Takahashi RN. A current overview of cannabinoids and glucocorticoids in facilitating extinction of aversive memories: potential extinction enhancers. Neuropharmacology 64: 389-395

Departamento de Farmacologia, Universidade Federal de Santa Catarina, Campus Trindade, 88040-900 Florianópolis, SC, Brazil. Electronic address: .
Neuropharmacology (Impact Factor: 4.82). 06/2012; 64(1):389-95. DOI: 10.1016/j.neuropharm.2012.05.039
Source: PubMed

ABSTRACT Emotional learning is extremely important for the survival of an individual. However, once acquired, emotional associations are not always expressed. The regulation of emotional responses under different environmental conditions is essential for mental health. Indeed, pathologic feelings of fear and anxiety are defining features of many serious psychiatric illness, including post-traumatic stress disorder (PTSD) and specific phobias. The simplest form of regulation of emotional responses is extinction, in which the conditioned response to a stimulus decreases when reinforcement (stimulus) is omitted. In addition to modulating basal anxiety states, recent studies suggest an important role for the endocannabinoid (eCB) and glucocorticoid systems in the modulation of emotional states and extinction of aversive memories in animals. The purpose of this review is to briefly outline the animal models of fear extinction and to describe how these have been used to examine the potential of extinction enhancing agents which specifically alter the eCB and glucocorticoid systems. Pharmacological manipulations of these systems by agents such as cannabinoid or glucocorticoid agonists can enhance the extinction process and avoid the retention of memories which have the potential to trigger trauma. A better understanding of these findings through animal models highlights the possibilities of using combined extinction enhancing agents in exposure-based psychotherapies for anxiety disorders related to inappropriate retention of aversive memories. This article is part of a special issue entitled 'Cognitive Enhancers'.

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Available from: Fabrício A Pamplona, Aug 27, 2014
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    • "It has been suggested that glucocorticoids recruit eCB signaling in the BLA and hippocampus to modulate aversive memory consolidation (Atsak et al, 2012; Campolongo et al, 2009). Moreover, de Bitencourt et al (2013) suggested that eCBs are recruited by glucocorticoids in the process of extinction of aversive memories. We have recently found that GRs in the BLA and hippocampus mediate the preventive effects of WIN55,212-2 on contextual extinction after an acute stressful experience. "
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    ABSTRACT: Most psychiatric disorders are characterized by emotional memory or learning disturbances. Chronic mild stress (CMS) is a common animal model for stress-induced depression. Here we examined whether 3 days of treatment using the CB1/2 receptor agonist WIN55,212-2 could ameliorate the effects of CMS on emotional learning (ie, conditioned avoidance and extinction), long-term potentiation (LTP) in the hippocampal-accumbens pathway, and depression-like symptoms (ie, coping with stress behavior, anhedonia, and weight changes). We also examined whether the ameliorating effects of WIN55,212-2 on behavior and physiology after CMS are mediated by CB1 and glucocorticoid receptors (GRs). Rats were exposed to CMS or handled on days 1–21. The agonist WIN55,212-2 or vehicle were administered on days 19–21 (IP; 0.5 mg/kg) and behavioral and electrophysiological measures were taken on days 23 and 28. The CB1 receptor antagonist AM251 (IP; 0.3 mg/kg) or the GR antagonist RU-38486 (IP; 10 mg/kg) were co-administered with WIN55,212-2. Our results show that CMS significantly modified physiological and behavioral reactions, as observed by the impairment in avoidance extinction and LTP in the hippocampal-accumbens pathway, and the alterations in depression-like symptoms, such as coping with stress behavior, weight gain, and sucrose consumption. The most significant effect observed in this study was that 3 days of WIN55,212-2 administration prevented the CMS-induced alterations in emotional memory (ie, extinction) and plasticity. This effect was mediated by CB1 receptors as the CB1 receptor antagonist AM251 prevented the ameliorating effects of WIN55,212-2 on extinction and LTP. The GR antagonist RU-38486 also prevented the CMS-induced alterations in extinction and plasticity, and when co-administered with WIN55,212-2, the preventive effects after CMS were maintained. The findings suggest that enhancing cannabinoid signaling could represent a novel approach to the treatment of cognitive deficits that accompany stress-related depression. Neuropsychopharmacology advance online publication, 13 November 2013; doi:10.1038/npp.2013.292
    Neuropsychopharmacology 03/2014; 96. · 7.83 Impact Factor
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    • "It has been suggested that glucocorticoids recruit eCB signaling in the BLA and hippocampus to modulate aversive memory consolidation (Atsak et al, 2012; Campolongo et al, 2009). Moreover, de Bitencourt et al (2013) suggested that eCBs are recruited by glucocorticoids in the process of extinction of aversive memories. We have recently found that GRs in the BLA and hippocampus mediate the preventive effects of WIN55,212-2 on contextual extinction after an acute stressful experience. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Most psychiatric disorders are characterized by emotional memory or learning disturbances. Chronic mild stress (CMS) is a common animal model for stress induced depression. Here we examined whether 3 days of treatment using the CB1/2 receptor agonist WIN55,212-2 could ameliorate the effects of CMS on emotional learning (ie, conditioned avoidance and extinction), long-term potentiation (LTP) in the hippocampal-accumbens pathway and depression-like symptoms (ie, coping with stress behavior, anhedonia and weight changes). We also examined whether the ameliorating effects of WIN55,212-2 on behavior and physiology after CMS are mediated by CB1 and glucocorticoid receptors (GRs). Rats were exposed to CMS or handled on days 1-21. The agonist WIN55,212-2 or vehicle were administered on days 19-21 (IP; 0.5 mg/kg) and behavioral and electrophysiological measures were taken on days 23 and 28. The CB1 receptor antagonist AM251 (IP; 0.3 mg/kg) or the GR antagonist RU-38486 (IP; 10 mg/kg) were co-administered with WIN55,212-2. Our results show that CMS significantly modified physiological and behavioral reactions, as observed by the impairment in avoidance extinction and LTP in the hippocampal-accumbens pathway, and the alterations in depression-like symptoms such as coping with stress behavior, weight gain and sucrose consumption. The most significant effect observed in this study was that 3 days of WIN55,212-2 administration prevented the CMS-induced alterations in emotional memory (ie, extinction) and plasticity. This effect was mediated by CB1 receptors as the CB1 receptor antagonist AM251 prevented the ameliorating effects of WIN55,212-2 on extinction and LTP. The GR antagonist RU-38486 also prevented the CMS-induced alterations in extinction and plasticity and when co-administered with WIN55,212-2, the preventive effects after CMS were maintained. The findings suggest that enhancing cannabinoid signaling could represent a novel approach to the treatment of cognitive deficits that accompany stress-related depression.Neuropsychopharmacology accepted article preview online, 21 October 2013. doi:10.1038/npp.2013.292.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2013; 39(4). DOI:10.1038/npp.2013.292 · 7.83 Impact Factor
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    • "Activating the eCB system can facilitate fear extinction in different behavioral tasks (Chhatwal et al., 2005; Pamplona et al., 2006; Pamplona et al., 2008; Bitencourt et al., 2008; de Oliveira Alvares et al., 2008; Abush and Akirav, 2010), whereas inhibition of eCB transmission robustly inhibit (or prolong) fear extinction (Marsicano et al., 2002; Suzuki et al., 2004; Pamplona et al., 2006; Ganon-Elazar and Akirav, 2009; Abush and Akirav, 2010). Similarly, studies in animals and humans have shown that glucocorticoids can facilitate extinction processes whereas GR antagonists impair extinction of conditioned fear (Barrett and Gonzalez-Lima, 2004; Yang et al., 2006; Yang et al., 2007; Ninomiya et al., 2010; Blundell et al., 2011; Clay et al., 2011; de Quervain et al., 2011; and see Bitencourt et al., 2013). Human studies suggest that the administration of cortisol can enhance extinctionbased psychotherapy (Aerni et al., 2004; de Quervain et al., 2011) and animal studies demonstrate that GR agonists can facilitate the extinction of contextual fear and fear potentiated-startle (Cai et al., 2006; Yang et al., 2006; Ninomiya et al., 2010; Blundell et al., 2011). "
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    ABSTRACT: Please cite this article in press as: Ganon-Elazar, E., Akirav, I., Cannabinoids and traumatic stress modulation of contextual fear extinction and GR expression in the amygdala-hippocampal-prefrontal circuit. Psychoneuroendocrinology (2013), Summary Considerable evidence suggests that cannabinoids modulate the behavioral and physiological response to stressful events. We have recently shown that activating the cannabi-noid system using the CB1/CB2 receptor agonist WIN55,212-2 (WIN) in proximity to exposure to single-prolonged stress (SPS), a rat model of emotional trauma, prevented the stress-induced enhancement of acoustic startle response, the impairment in avoidance extinction and the enhanced negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis (Ganon-Elazar and Akirav, 2012). Some of the effects were found to be mediated by CB1 receptors in the basolateral amygdala (BLA). Here we examined whether cannabinoid receptor activation in a putative brain circuit that includes the BLA, hippocampus and prefrontal cortex (PFC), could prevent the effects of traumatic stress on contextual fear extinction and alterations in glucocorticoid receptor (GR) protein levels. We found that: (i) SPS impaired contextual fear extinction tested one week after trauma exposure and that WIN prevented the stress-induced impairment of extinction when microin-jected immediately after trauma exposure into the BLA or hippocampus (5 mg), but not when microinjected into the PFC, (ii) the ameliorating effects of WIN on contextual extinction were prevented by blocking GRs in the BLA and hippocampus, and (iii) SPS up regulated GRs in the BLA, PFC and hippocampus and systemic WIN administration (0.5 mg/kg) after trauma exposure normalized GR levels in the BLA and hippocampus, but not in the PFC. Cannabinoid receptor activation in the aftermath of trauma exposure may regulate the emotional response to the trauma and prevent stress-induced impairment of extinction and GR up regulation through the mediation of CB1 receptors in the BLA and hippocampus. Taken together, the findings suggest that the interaction between the cannabinoid and glucocorticoid systems is crucial in the modulation of emotional trauma.
    Psychoneuroendocrinology 09/2013; 38(9):1675-87. · 5.59 Impact Factor
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