Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418: 530-534

Molecular Genetics of Behaviour, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany.
Nature (Impact Factor: 41.46). 09/2002; 418(6897):530-4. DOI: 10.1038/nature00839
Source: PubMed


Acquisition and storage of aversive memories is one of the basic principles of central nervous systems throughout the animal kingdom. In the absence of reinforcement, the resulting behavioural response will gradually diminish to be finally extinct. Despite the importance of extinction, its cellular mechanisms are largely unknown. The cannabinoid receptor 1 (CB1) and endocannabinoids are present in memory-related brain areas and modulate memory. Here we show that the endogenous cannabinoid system has a central function in extinction of aversive memories. CB1-deficient mice showed strongly impaired short-term and long-term extinction in auditory fear-conditioning tests, with unaffected memory acquisition and consolidation. Treatment of wild-type mice with the CB1 antagonist SR141716A mimicked the phenotype of CB1-deficient mice, revealing that CB1 is required at the moment of memory extinction. Consistently, tone presentation during extinction trials resulted in elevated levels of endocannabinoids in the basolateral amygdala complex, a region known to control extinction of aversive memories. In the basolateral amygdala, endocannabinoids and CB1 were crucially involved in long-term depression of GABA (gamma-aminobutyric acid)-mediated inhibitory currents. We propose that endocannabinoids facilitate extinction of aversive memories through their selective inhibitory effects on local inhibitory networks in the amygdala.

Download full-text


Available from: Jianrong Tang, Oct 08, 2014
  • Source
    • "In the present study, administration of the anandamide metabolism inhibitor , URB, to WT mice attenuated freezing behavior and facilitated fear extinction, whereas the selective CB1 antagonist, AM281, increased freezing behavior. Even if there are contradictory results (Mikics et al., 2006), several studies show that pharmacological antagonist or genetic deletion of CB1 receptors increases freezing behavior and impairs extinction in fear conditioning models (Marsicano et al., 2002; Suzuki et al., 2004; Varvel et al., 2005; Kamprath et al., 2006; Niyuhire et al., 2007; Reich et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Inducible (iNOS) or neuronal (nNOS) nitric oxide synthase gene deletion increases or decreases anxiety-like behavior in mice, respectively. Since NO and endocannabinoids (ECBs) interact to modulate defensive behavior, the former effect could involve a compensatory increase in basal brain NOS activity and/or changes in the ECB system. Thus, we investigated the expression and extinction of contextual fear conditioning (CFC) of iNOS knockout (KO) mice and possible involvement of ECBs in these responses. Methods: We evaluated the effects of a preferential nNOS inhibitor, 7-nitroindazol (7-NI), NOS activity and mRNA changes of nitrergic and ECB systems components in the medial prefrontal cortex (MPFC) and hippocampus (HIP) of wild-type (WT) and KO mice. The effects of URB597, an inhibitor of the FAAH enzyme, which metabolize the ECB anandamide, WIN55,212-2, a non-selective cannabinoid agonist, and AM281, a selective CB1 antagonist, on CFC were also evaluated. Results: CFC expression was similar in WT and KO mice, but KO presented extinction deficits and increased basal NOS activity in the MPFC. 7-NI decreased fear expression and facilitated extinction in WT and KO mice. URB597 decreased fear expression in WT mice and facilitated extinction in KO mice whereas WIN and AM281 increased it in WT mice. Non-conditioned KO mice showed changes in the mRNA expression of nitrergic and ECB system components in the MPFC and HIP that were modified by fear conditioning. Conclusion: These data reinforce the involvement of the NO and ECBs (anandamide) in stress-related disorders and point out to a deregulation of the ECB system in situations where NO signaling is increased. nitric oxide7-nitroindazoleURB597WIN55212-2AM281anandamideCB1 receptorsfear conditioningextinction © The Author 2014. Published by Oxford University Press on behalf of CINP.
    Full-text · Article · Jan 2015 · The International Journal of Neuropsychopharmacology
  • Source
    • "Identification and better characterization of the ECB system led to the development of pharmacological agents that increase cannabinoid signaling, potentially being future new tools to treat anxiety-related disorders (Hill and Patel, 2013). Even if the effects of cannabinoid drugs on emotional related behaviors appear to be highly influenced by the experimental context (Haller et al., 2009; Manduca et al., 2014; Naidu et al., 2007), several studies showed anxiolytic effects (Haller et al., 2004; Rey et al., 2012) and facilitated extinction of aversion-related memories (Marsicano et al., 2002; Metna-Laurent et al., 2012) by CB1 receptors activation. The anxiolytic effects of AM404 or FAAH inhibitors systemically administrated are paralleled by increases in AEA concentrations in brain regions that include the PFC (Bortolato et al., 2006; Kathuria et al., 2003), indicating this structure could be involved in these effects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Endocannabinoids (ECBs) such as anandamide (AEA) act by activating cannabinoid type 1 (CB1) or 2 (CB2) receptors. The anxiolytic effect of drugs that facilitate ECB effects is associated with increase in AEA levels in several encephalic areas, including the prefrontal cortex (PFC). Activation of CB1 receptors by CB1 agonists injected directly into these areas is usually anxiolytic. However, depending on the encephalic region being investigated and on the stressful experiences, opposite effects were observed, as reported in the ventral HIP. In addition, contradictory results have been reported after CB1 activation in the dorsal HIP (dHIP). Therefore, in the present paper we have attempted to verify if directly interfering with ECB metabolism/reuptake in the prelimbic (PL) portion of the medial PFC (MPFC) and dHIP would produce different effects in two conceptually distinct animal models: the elevated plus maze (EPM) and the Vogel conflict test (VCT). We observed drugs which interfere with ECB reuptake/metabolism in both the PL and in the dentate gyrus of the dHIP induced anxiolytic-like effect, in both the EPM and in the VCT via CB1 receptors, suggesting CB1 signaling in these brain regions modulate defensive responses to both innate and learned threatening stimuli. This data further strengthens previous results indicating modulation of hippocampal and MPFC activity via CB1 by ECBs, which could be therapeutically targeted to treat anxiety disorders. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jan 2015 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
  • Source
    • "These emotionbased changes suggest the endocannabinoid system is involved with emotional processing. Cannabinoid receptors are important in processing emotional material (Marsicano et al., 2002) and are abundant in limbic regions including the amygdala, cingulate cortex and hippocampus, as well as the frontal cortex (Pamplona and Takahashi, 2012). Cannabis consists of over 100 cannabinoids , the two most abundant being THC, a partial agonist at the CB1 receptor (Pertwee, 2008) and cannabidiol (CBD) which has a complex mode of action involving several receptor, re-uptake and enzymatic proteins. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute administration of the primary psychoactive constituent of cannabis, Δ-9-tetrahydrocannabinol (THC), impairs human facial affect recognition, implicating the endocannabinoid system in emotional processing. Another main constituent of cannabis, cannabidiol (CBD), has seemingly opposite functional effects on the brain. This study aimed to determine the effects of THC and CBD, both alone and in combination on emotional facial affect recognition. 48 volunteers, selected for high and low frequency of cannabis use and schizotypy, were administered, THC (8mg), CBD (16mg), THC+CBD (8mg+16mg) and placebo, by inhalation, in a 4-way, double-blind, placebo-controlled crossover design. They completed an emotional facial affect recognition task including fearful, angry, happy, sad, surprise and disgust faces varying in intensity from 20% to 100%. A visual analogue scale (VAS) of feeling 'stoned' was also completed. In comparison to placebo, CBD improved emotional facial affect recognition at 60% emotional intensity; THC was detrimental to the recognition of ambiguous faces of 40% intensity. The combination of THC+CBD produced no impairment. Relative to placebo, both THC alone and combined THC+CBD equally increased feelings of being 'stoned'. CBD did not influence feelings of 'stoned'. No effects of frequency of use or schizotypy were found. In conclusion, CBD improves recognition of emotional facial affect and attenuates the impairment induced by THC. This is the first human study examining the effects of different cannabinoids on emotional processing. It provides preliminary evidence that different pharmacological agents acting upon the endocannabinoid system can both improve and impair recognition of emotional faces. Copyright © 2014. Published by Elsevier B.V.
    Full-text · Article · Dec 2014 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
Show more