Article

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: 5.11). 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
    Full-text · Article · Mar 2014 · Neuropsychopharmacology
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    • "However, similar to Y-maze performance, there was no effect of chronic CP treatment, strengthening the selectivity of its action on PPI. Thus, although previous studies have shown involvement of both the endocannabinoid system and BDNF in memory formation and consolidation (Papaleo et al., 2011; Panlilio et al., 2012; De Bitencourt et al., 2013; Wright et al., 2013), in our protocol including chronic CP treatment followed by a 2-week washout, there were no such effects. Future studies could include the acute effects of cannabinoid receptor stimulation on memory function in BDNF HET mice and controls after chronic pre-treatment with CP, similar to the PPI studies presented here. "
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    ABSTRACT: Reduced brain-derived neurotrophic factor (BDNF) signaling has been shown in the frontal cortex and hippocampus in schizophrenia. The aim of the present study was to investigate whether a BDNF deficit would modulate effects of chronic cannabis intake, a well-described risk factor for schizophrenia development. BDNF heterozygous mice (HET) and wild-type controls were chronically treated during weeks 6, 7, and 8 of life with the cannabinoid receptor agonist, CP55,940 (CP). After a 2-week delay, there were no CP-induced deficits in any of the groups in short-term spatial memory in a Y-maze task or novel object recognition memory. Baseline prepulse inhibition (PPI) was lower but average startle was increased in BDNF HET compared to wild-type controls. Acute CP administration before the PPI session caused a marked increase in PPI in male HET mice pre-treated with CP but not in any of the other male groups. In females, there were small increases of PPI in all groups upon acute CP administration. Acute CP administration furthermore reduced startle and this effect was greater in HET mice irrespective of chronic CP pre-treatment. Analysis of the levels of [(3)H]CP55,940 binding by autoradiography revealed a significant increase in the nucleus accumbens of male BDNF HET mice previously treated with CP but not in any of the other groups or in the caudate nucleus. These results show that BDNF deficiency and chronic young-adult cannabinoid receptor stimulation do not interact in this model on learning and memory later in life. In contrast, male "two hit" mice, but not females, were hypersensitive to the effect of acute CP on sensorimotor gating. These effects may be related to a selective increase of [(3)H]CP55,940 binding in the nucleus accumbens, reflecting up-regulation of CB1 receptor density in this region. These data could be of relevance to our understanding of differential "two hit" neurodevelopmental mechanisms in schizophrenia.
    Full-text · Article · Oct 2013 · Frontiers in Behavioral Neuroscience
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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.
    Full-text · Article · Oct 2013 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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