Abstract
Exposure to a traumatic event may result in the development of post-traumatic stress disorder (PTSD). Endocannabinoids are crucial modulators of the stress response, interfere with excessive retrieval and facilitate the extinction of traumatic memories. Exposure therapy, combined with pharmacotherapy, represents a promising tool for PTSD treatment. We investigated whether pharmacological manipulations of the endocannabinoid system during extinction learning ameliorates the behavioral changes induced by trauma exposure. Rats were exposed to inescapable footshocks paired with social isolation, a risk factor for PTSD. One week after trauma, rats were subjected to three spaced extinction sessions, mimicking human exposure therapy. The anandamide hydrolysis inhibitor URB597, the 2-arachidonoylglycerol hydrolysis inhibitor JZL184 or the cannabinoid agonist WIN55,212-2 were administered before or after the extinction sessions. Rats were tested for extinction retention 16 or 36 days after trauma and 24-h later for social interaction. Extinction training alone reduced fear of the trauma-associated context but did not restore normal social interaction. Traumatized animals not exposed to extinction sessions exhibited reductions in hippocampal anandamide content with respect to home-cage controls. Noteworthy, all drugs exerted beneficial effects, but URB597 (0.1 mg/kg) induced the best improvements by enhancing extinction consolidation and restoring normal social behavior in traumatized rats through indirect activation of CB1 receptors. The ameliorating effects remained stable long after treatment and trauma exposure. Our findings suggest that drugs potentiating endocannabinoid neurotransmission may represent promising tools when combined to exposure-based psychotherapies in the treatment of PTSD.
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References
Abramowitz JS (2013). The practice of exposure therapy: relevance of cognitive-behavioral theory and extinction theory. Behav Ther 44: 548–558.
American Psychiatric Association American Psychiatric Association; (2013) Diagnosticand Statistical Manual of Mental Disorders.
Atsak P, Hauer D, Campolongo P, Schelling G, McGaugh JL, Roozendaal B (2012). Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory. Proc Natl Acad Sci USA 109: 3504–3509.
Berardi A, Trezza V, Palmery M, Trabace L, Cuomo V, Campolongo P (2014). An updated animal model capturing both the cognitive and emotional features of post-traumatic stress disorder (PTSD). Front Behav Neurosci 8: 142.
Bisson JI, Roberts NP, Andrew M, Cooper R, Lewis C (2013). Psychological therapies for chronic post-traumatic stress disorder (PTSD) in adults. Cochrane database Syst Rev CD003388.
Bitencourt RM, Pamplona FA, Takahashi RN (2014). Corticosteroid-endocannabinoid loop supports decrease of fear-conditioned response in rats. Eur Neuropsychopharmacol 24: 1091–1102.
Bowers ME, Ressler KJ (2015). Interaction between the cholecystokinin and endogenous cannabinoid systems in cued fear expression and extinction retention. Neuropsychopharmacology 40: 688–700.
Bowles NP, Hill MN, Bhagat SM, Karatsoreos IN, Hillard CJ, McEwen BS (2012). Chronic, noninvasive glucocorticoid administration suppresses limbic endocannabinoid signaling in mice. Neuroscience 204: 83–89.
Campolongo P, Morena M, Scaccianoce S, Trezza V, Chiarotti F, Schelling G et al (2013). Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity. Neuropsychopharmacology 38: 1276–1286.
Chen X, Li Y, Li S, Kirouac GJ (2012). Early fear as a predictor of avoidance in a rat model of post-traumatic stress disorder. Behav Brain Res 226: 112–117.
Chhatwal JP, Davis M, Maguschak KA, Ressler KJ (2005). Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacology 30: 516–524.
Choi DC, Rothbaum BO, Gerardi M, Ressler KJ (2010). Pharmacological enhancement of behavioral therapy: focus on posttraumatic stress disorder. Curr Top Behav Neurosci 2: 279–299.
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996). Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384: 83–87.
de Quervain DJ-F, Bentz D, Michael T, Bolt OC, Wiederhold BK, Margraf J et al (2011). Glucocorticoids enhance extinction-based psychotherapy. Proc Natl Acad Sci USA 108: 6621–6625.
Di Marzo V (1999). Biosynthesis and inactivation of endocannabinoids: relevance to their proposed role as neuromodulators. Life Sci 65: 645–655.
Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL et al (2002). Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99: 10819–10824.
Furini C, Myskiw J, Izquierdo I (2014). The learning of fear extinction. Neurosci Biobehav Rev 47: 670–683.
Gunduz-Cinar O, MacPherson KP, Cinar R, Gamble-George J, Sugden K, Williams B et al (2013). Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry 18: 813–823.
Gutner CA, Gallagher MW, Baker AS, Sloan DM, Resick PA (2016). Time course of treatment dropout in cognitive-behavioral therapies for posttraumatic stress disorder. Psychol Trauma 8: 115–121.
Haller J, Barna I, Barsvari B, Gyimesi Pelczer K, Yasar S, Panlilio L V. et al (2009). Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats. Psychopharmacology (Berl) 204: 607–616.
Hauer D, Ratano P, Morena M, Scaccianoce S, Briegel I, Palmery M et al (2011). Propofol enhances memory formation via an interaction with the endocannabinoid system. Anesthesiology 114: 1380–1388.
Heim C, Nemeroff CB (2009). Neurobiology of posttraumatic stress disorder. CNS Spectr 14: 13–24.
Hill MN, Campolongo P, Yehuda R, Patel S (2017). Integrating endocannabinoid signaling and cannabinoids into the biology and treatment of posttraumatic stress disorder. Neuropsychopharmacology 43: 80–102.
Hill MN, Carrier EJ, Ho W-SV, Shi L, Patel S, Gorzalka BB et al (2008a). Prolonged glucocorticoid treatment decreases cannabinoid CB1 receptor density in the hippocampus. Hippocampus 18: 221–226.
Hill MN, Miller GE, Ho W-S V, Gorzalka BB, Hillard CJ (2008b). Serum endocannabinoid content is altered in females with depressive disorders: a preliminary report. Pharmacopsychiatry 41: 48–53.
Hofmann SG (2007). Enhancing exposure-based therapy from a translational research perspective. Behav Res Ther 45: 1987–2001.
Holmes A, Singewald N (2013). Individual differences in recovery from traumatic fear. Trends Neurosci 36: 23–31.
Hoskins M, Pearce J, Bethell A, Dankova L, Barbui C, Tol WA et al (2015). Pharmacotherapy for post-traumatic stress disorder: systematic review and meta-analysis. Br J Psychiatry 206: 93–100.
Järbe TUC, DiPatrizio N V, Li C, Makriyannis A (2007). Effects of AM1346, a high-affinity CB1 receptor selective anandamide analog, on open-field behavior in rats. Behav Pharmacol 18: 673–680.
Jetly R, Heber A, Fraser G, Boisvert D (2015). The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: a preliminary randomized, double-blind, placebo-controlled cross-over design study. Psychoneuroendocrinology 51: 585–588.
Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M (2009). Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89: 309–380.
Kathuria S, Gaetani S, Fegley D, Valiño F, Duranti A, Tontini A et al (2003). Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9: 76–81.
Korem N, Akirav I (2014). Cannabinoids prevent the effects of a footshock followed by situational reminders on emotional processing. Neuropsychopharmacology 39: 2709–2722.
Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE et al (2009). Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol 5: 37–44.
Manduca A, Lassalle O, Sepers M, Campolongo P, Cuomo V, Marsicano G et al (2016). Interacting cannabinoid and opioid receptors in the nucleus accumbens core control adolescent social play. Front Behav Neurosci 10: 211.
Manduca A, Morena M, Campolongo P, Servadio M, Palmery M, Trabace L et al (2015). Distinct roles of the endocannabinoids anandamide and 2-arachidonoylglycerol in social behavior and emotionality at different developmental ages in rats. Eur Neuropsychopharmacol 25: 1362–1374.
Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG et al (2002). The endogenous cannabinoid system controls extinction of aversive memories. Nature 418: 530–534.
Matsuda S, Matsuzawa D, Ishii D, Tomizawa H, Shimizu E (2014). Effects of memory age and interval of fear extinction sessions on contextual fear extinction. Neurosci Lett 578: 139–142.
McGuire JF, Lewin AB, Storch EA (2014). Enhancing exposure therapy for anxiety disorders, obsessive-compulsive disorder and post-traumatic stress disorder. Expert Rev Neurother 14: 893–910.
Micale V, Stepan J, Jurik A, Pamplona FA, Marsch R, Drago F et al (2017). Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus. J Psychiatr Res 90: 46–59.
Milad MR, Quirk GJ (2012). Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 63: 129–151.
Moore SA (2009). Cognitive abnormalities in posttraumatic stress disorder. Curr Opin Psychiatry 22: 19–24.
Morena M, Campolongo P (2014). The endocannabinoid system: An emotional buffer in the modulation of memory function. Neurobiol Learn Mem 112: 30–43.
Morena M, De Castro V, Gray JM, Palmery M, Trezza V, Roozendaal B et al (2015). Training-associated emotional arousal shapes endocannabinoid modulation of spatial memory retrieval in rats. J Neurosci 35: 13962–13974.
Morena M, Leitl KD, Vecchiarelli HA, Gray JM, Campolongo P, Hill MN (2016a). Emotional arousal state influences the ability of amygdalar endocannabinoid signaling to modulate anxiety. Neuropharmacology 111: 59–69.
Morena M, Patel S, Bains JS, Hill MN (2016b). Neurobiological interactions between stress and the endocannabinoid system. Neuropsychopharmacology 41: 80–102.
Pamplona FA, Bitencourt RM, Takahashi RN (2008). Short- and long-term effects of cannabinoids on the extinction of contextual fear memory in rats. Neurobiol Learn Mem 90: 290–293.
Parsons RG, Ressler KJ (2013). Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci 16: 146–153.
Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR et al (2006). Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev 12: 21–38.
Qi M, Morena M, Vecchiarelli HA, Hill MN, Schriemer DC (2015). A robust capillary liquid chromatography/tandem mass spectrometry method for quantitation of neuromodulatory endocannabinoids. Rapid Commun Mass Spectrom 29: 1889–1897.
Quirk GJ, Paré D, Richardson R, Herry C, Monfils MH, Schiller D et al (2010). Erasing fear memories with extinction training. J Neurosci 30: 14993–14997.
Rabinak CA, Phan KL (2014). Cannabinoid modulation of fear extinction brain circuits: a novel target to advance anxiety treatment. Curr Pharm Des 20: 2212–2217.
Robinson L, Hinder L, Pertwee RG, Riedel G (2003). Effects of delta9-THC and WIN-55,212-2 on place preference in the water maze in rats. Psychopharmacology (Berl) 166: 40–50.
Sciolino NR, Zhou W, Hohmann AG (2011). Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats. Pharmacol Res 64: 226–234.
Shoshan N, Segev A, Abush H, Mizrachi Zer-Aviv T, Akirav I (2017). Cannabinoids prevent the differential long-term effects of exposure to severe stress on hippocampal- and amygdala-dependent memory and plasticity. Hippocampus 27: 1093–1109.
Singewald N, Schmuckermair C, Whittle N, Holmes A, Ressler KJ (2015). Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. Pharmacol Ther 149: 150–190.
Trezza V, Campolongo P (2013). The endocannabinoid system as a possible target to treat both the cognitive and emotional features of post-traumatic stress disorder (PTSD). Front Behav Neurosci 7: 100.
Wang M, Hill MN, Zhang L, Gorzalka BB, Hillard CJ, Alger BE (2012). Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation. J Psychopharmacol 26: 56–70.
Wheeler AL, Teixeira CM, Wang AH, Xiong X, Kovacevic N, Lerch JP et al (2013). Identification of a functional connectome for long-term fear memory in mice. PLoS Comput Biol 9: e1002853.
Acknowledgements
We thank Daniela Valeri, Maria Grazia Coseglia, Sonia Frusciante and Nicoletta Marinelli for technical help, and the Southern Alberta Mass Spectrometry Centre, located in and supported by the Cumming School of Medicine, University of Calgary, for their services in targeted liquid chromatography tandem mass spectrometry.
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Morena, M., Berardi, A., Colucci, P. et al. Enhancing Endocannabinoid Neurotransmission Augments The Efficacy of Extinction Training and Ameliorates Traumatic Stress-Induced Behavioral Alterations in Rats. Neuropsychopharmacol. 43, 1284–1296 (2018). https://doi.org/10.1038/npp.2017.305
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DOI: https://doi.org/10.1038/npp.2017.305
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