Exercise-induced increases in Anandamide and BDNF during extinction consolidation contribute to reduced threat following reinstatement: Preliminary evidence from a randomized controlled trial

Kevin M Crombie, Anneliis Sartin-Tarm, Kyrie Sellnow, Rachel Ahrenholtz, Sierra Lee, Megan Matalamaki, Neda E Almassi, Cecilia J Hillard, Kelli F Koltyn, Tom G Adams, Josh M Cisler, Kevin M Crombie, Anneliis Sartin-Tarm, Kyrie Sellnow, Rachel Ahrenholtz, Sierra Lee, Megan Matalamaki, Neda E Almassi, Cecilia J Hillard, Kelli F Koltyn, Tom G Adams, Josh M Cisler

Abstract

Introduction: We recently demonstrated that moderate-intensity aerobic exercise delivered during the consolidation of fear extinction learning reduced threat expectancy during a test of extinction recall among women with posttraumatic stress disorder (PTSD). These findings suggest that exercise may be a potential candidate for improving the efficacy of exposure-based therapies, which are hypothesized to work via the mechanisms of fear extinction learning. The purpose of this secondary analysis was to examine whether exercise-induced increases in circulating concentrations of candidate biomarkers: endocannabinoids (anandamide [AEA]; 2-arachidonoylglycerol [2-AG], brain-derived neurotrophic factor (BDNF), and homovanillic acid (HVA), mediate the effects of exercise on extinction recall.

Methods: Participants (N = 35) completed a 3-day fear acquisition (day 1), extinction (day 2), and extinction recall (day 3) protocol, in which participants were randomly assigned to complete either moderate-intensity aerobic exercise (EX) or a light-intensity control (CON) condition following extinction training (day 2). Blood was obtained prior to and following EX or CON. Threat expectancy ratings during tests of extinction recall (i.e., initial fear recall and fear recall following reinstatement) were obtained 24 h following EX or CON. Mediation was tested using linear-mixed effects models and bootstrapping of the indirect effect.

Results: Circulating concentrations of AEA and BDNF (but not 2-AG and HVA) were found to mediate the relationship between moderate-intensity aerobic exercise and reduced threat expectancy ratings following reinstatement (AEA 95% CI: -0.623 to -0.005; BDNF 95% CI: -0.941 to -0.005).

Conclusions: Exercise-induced increases in peripheral AEA and BDNF appear to play a role in enhancing consolidation of fear extinction learning, thereby leading to reduced threat expectancies following reinstatement among women with PTSD. Future mechanistic research examining these and other biomarkers (e.g., brain-based biomarkers) is warranted.

Keywords: Aerobic exercise; Brain-derived neurotrophic factor; Endocannabinoids; Exposure-therapy; Fear extinction; Posttraumatic stress disorder.

Conflict of interest statement

Conflicts of Interest: CJH is a member of the Scientific Advisory Board of Phytecs, Inc. and has an equity position in Formulate Biosciences. KMC, AS-T, KS, RA, SL, MM, NEA, KFK, TGA, and JMC have no conflicts of interest.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1.
Figure 1.
Graphical overview of the study design. On Day 1, participants completed a fear acquisition task in which the CS+ was paired with a shock (US) with 50% probability. On Day 2 (24hrs later), participants completed a fear extinction task in a distinct context (i.e., different background color) during which the CS+ was no longer paired with US. Immediately after completing the task, half of the participants were randomly assigned to complete 30-min of moderate-intensity aerobic exercise (EX) on a treadmill or 30-min of very-light intensity walking (CON) on a treadmill. Blood draws (to assess circulating concentrations of AEA, 2-AG, BDNF, and HVA) occurred immediately prior to and following the experimental manipulation on day 2. Participants returned on Day 3 (24 hrs later) for a fear extinction recall test alternating between acquisition and extinction contexts (i.e., initial fear recall). A single US was then presented (i.e., reinstatement procedure), followed by another recall test alternating between acquisition and extinction contexts. Threat expectancy ratings during extinction recall were provided once before the initial fear recall test, and immediately after our reinstatement procedure (i.e., prior to the second extinction recall test).
Figure 2.
Figure 2.
Circulating concentrations of AEA (A), 2-AG (B), BDNF (C), and HVA (D) prior to and following the light-intensity control condition and moderate-intensity aerobic exercise. In addition to estimating regression coefficients for path a, exploratory post hoc paired samples t-tests were also conducted to further examine circulating concentrations of AEA, 2-AG, BDNF, and HVA prior to and following light-intensity (CON) or moderate-intensity aerobic exercise (EX). There was a significant increase (denoted *) in circulating concentrations of AEA following EX (t(13)=4.21,p = .001, d = 0.58), but not CON (t(13)=−0.66, p = .523,d = −0.16; see figure 2a); along with a significant increase in circulating concentrations of BDNF following EX (t(12)=2.39, p = .034, d = 0.92), but not CON (t(11)=−0.71, p = .494, d = −0.18; see figure 2c); and a significant increase in circulating concentrations of HVA following EX (t(12)=3.71, p = .003, d = 0.94), but not CON (t(11)=1.39, p = .191,d = 0.33; see figure 2d). There was not a significant increase in circulating concentrations of 2-AG following EX (t(13)=−.157, p =.878,d = −0.01) or CON (t(13)=0.922,p=.373, d = 0.20; see figure 2b).
Figure 3.
Figure 3.
Mediation Models for AEA and 2-AG. Mediation model for AEA (A) along with corresponding histogram of bootstrapped indirect effects and 95% CI (B) indicated that circulating concentrations of AEA mediated the relationship between aerobic exercise and reduced threat expectancy ratings following reinstatement. Mediation model for 2-AG (C), along with corresponding histogram of bootstrapped indirect effects and 95% CI (D) indicated that circulating concentrations of 2-AG did not mediate the relationship between aerobic exercise and reduced threat expectancy ratings following reinstatement. Values listed are standardized regression coefficients for path a (effect of independent variable on biomarker variable), path b (effect of biomarker variable on dependent variable), the indirect effect (product of regression coefficients for predictor variables in path a and b), path c (effect of independent variable on dependent variable without biomarker variable included in model), and path c’ (difference between direct and indirect effect). 95% CI for the indirect effect (used to determine if mediation occurred; denoted * for 95% CIs not containing zero) was obtained from bootstrap procedure involving resampling with replacement and 10,000 iterations.
Figure 4.
Figure 4.
Mediation Models for BDNF and HVA. Mediation model for BDNF (A) along with corresponding histogram of bootstrapped indirect effects and 95% CI (B) indicated that circulating concentrations of BDNF mediated the relationship between aerobic exercise and reduced threat expectancy ratings following reinstatement. Mediation model for HVA (C), along with corresponding histogram of bootstrapped indirect effects and 95% CI (D) indicated that circulating concentrations of HVA did not mediate the relationship between aerobic exercise and reduced threat expectancy ratings following reinstatement. Values listed are standardized regression coefficients for path a (effect of independent variable on biomarker variable), path b (effect of biomarker variable on dependent variable), the indirect effect (product of regression coefficients for predictor variables in path a and b), path c (effect of independent variable on dependent variable without biomarker variable included in model), and path c’ (difference between direct and indirect effect). 95% CI for the indirect effect (used to determine if mediation occurred; denoted * for 95% CIs not containing zero) was obtained from bootstrap procedure involving resampling with replacement and 10,000 iterations.

References

    1. Abraham AD, Neve KA, Lattal KM, 2016. Activation of D1/5 dopamine receptors: a common mechanism for enhancing extinction of fear and reward-seeking behaviors. Neuropsychopharmacology 41, 2072–2081. 10.1038/npp.2016.5
    1. Blanco C, Hoertel N, Wall MM, Franco S, Peyre H, Neria Y, Helpman L, Limosin F, 2018. Toward Understanding Sex Differences in the Prevalence of Posttraumatic Stress Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 79. 10.4088/JCP.16m11364
    1. Blevins CA, Weathers FW, Davis MT, Witte TK, Domino JL, 2015. The posttraumatic stress disorder checklist for DSM-5 (PCL-5): development and initial psychometric evaluation. J Trauma Stress 28, 489–498. 10.1002/jts.22059
    1. Bluett RJ, Gamble-George JC, Hermanson DJ, Hartley ND, Marnett LJ, Patel S, 2014. Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation. Transl Psychiatry 4, e408. 10.1038/tp.2014.53
    1. Bouchet CA, Miner MA, Loetz EC, Rosberg AJ, Hake HS, Farmer CE, Ostrovskyy M, Gray N, Greenwood BN, 2018. Activation of Nigrostriatal Dopamine Neurons during Fear Extinction Prevents the Renewal of Fear. Neuropsychopharmacology 43, 665–672. 10.1038/npp.2017.235
    1. Brellenthin AG, Crombie KM, Hillard CJ, Koltyn KF, 2017. Endocannabinoid and mood responses to exercise in adults with varying physical activity levels. Med Sci Sports Exer, 49, 1688–1696. 10.1249/MSS.0000000000001276
    1. Breslau N, Kessler RC, Chilcoat HD, Schultz LR, Davis GC, Andreski P, 1998. Trauma and posttraumatic stress disorder in the community: the 1996 Detroit Area Survey of Trauma. Arch Gen Psychiatry 55, 626–632. 10.1001/archpsyc.55.7.626
    1. Butovsky E, Juknat A, Goncharov I, Elbaz J, Eilam R, Zangen A, Vogel Z, 2005. In vivo up-regulation of brain-derived neurotrophic factor in specific brain areas by chronic exposure to Delta-tetrahydrocannabinol. J Neurochem 93, 802–811. 10.1111/j.1471-4159.2005.03074.x
    1. Cavener VS, Gaulden A, Pennipede D, Jagasia P, Uddin J, Marnett LJ, Patel S, 2018. Inhibition of diacylglycerol lipase impairs fear extinction in mice. Front Neurosci 12, 479. 10.3389/fnins.2018.00479
    1. Chang WH, Scheinin M, Burns RS, Linnoila M, 1983. Rapid and simple determination of homovanillic acid in plasma using high performance liquid chromatography with electrochemical detection. Acta Pharmacol Toxicol (Copenh) 53, 275–279. 10.1111/j.1600-0773.1983.tb03423.x
    1. Cheer JF, Wassum KM, Heien MLAV, Phillips PEM, Wightman RM, 2004. Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats. J Neurosci 24, 4393–4400. 10.1523/JNEUROSCI.0529-04.2004
    1. Chhatwal JP, Stanek-Rattiner L, Davis M, Ressler KJ, 2006. Amygdala BDNF signaling is required for consolidation but not encoding of extinction. Nat Neurosci 9, 870–872. 10.1038/nn1718
    1. Cisler JM, Bush K, Scott Steele J, Lenow JK, Smitherman S, Kilts CD, 2015. Brain and behavioral evidence for altered social learning mechanisms among women with assault-related posttraumatic stress disorder. J Psychiatr Res 63, 75–83. 10.1016/j.jpsychires.2015.02.014
    1. Cisler JM, Privratsky AA, Sartin-Tarm A, Sellnow K, Ross M, Weaver S, Hahn E, Herringa RJ, James GA, Kilts CD, 2020. L-DOPA and consolidation of fear extinction learning among women with posttraumatic stress disorder. Transl Psychiatry 10, 287. 10.1038/s41398-020-00975-3
    1. Crombie KM, Brellenthin AG, Hillard CJ, Koltyn KF, 2018. Psychobiological responses to aerobic exercise in individuals with posttraumatic stress disorder. J Trauma Stress 31, 134–145. 10.1002/jts.22253
    1. Crombie KM, Leitzelar BN, Brellenthin AG, Hillard CJ, & Koltyn KF, 2019. Loss of exercise- and stress-induced increases in circulating 2-arachidonoylglycerol concentrations in adults with chronic PTSD. Biol Psychol 145, 1–7. 10.1016/j.biopsycho.2019.04.002
    1. Crombie KM, Sartin-Tarm A, Sellnow K, Ahrenholtz R, Lee S, Matalamaki M, Adams TG, Cisler JM, 2021. Aerobic exercise and consolidation of fear extinction learning among women with posttraumatic stress disorder. Behav Res Ther 142, 10.1016/j.brat.2021.103867
    1. de Carvalho Myskiw J, Benetti F, Izquierdo I, 2013. Behavioral tagging of extinction learning. Proc Natl Acad Sci U S A 110, 1071–1076. 10.1073/pnas.1220875110
    1. de Carvalho Myskiw J, Furini CRG, Benetti F, Izquierdo I, 2014. Hippocampal molecular mechanisms involved in the enhancement of fear extinction caused by exposure to novelty. Proc Natl Acad Sci U S A 111, 4572–4577. 10.1073/pnas.1400423111
    1. Dincheva I, Drysdale AT, Hartley CA, Johnson DC, Jing D, King EC, Ra S, Gray JM, Yang R, DeGruccio AM, Huang C, Cravatt BF, Glatt CE, Hill MN, Casey BJ, Lee FS, 2015. FAAH genetic variation enhances fronto-amygdala function in mouse and human. Nat Commun 6, 6395. 10.1038/ncomms7395
    1. D’Souza DC, Pittman B, Perry E, Simen A, 2009. Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans. Psychopharmacology (Berl) 202, 569–578. 10.1007/s00213-008-1333-2
    1. Frey U, Morris RG, 1997. Synaptic tagging and long-term potentiation. Nature 385, 533–536. 10.1038/385533a0
    1. Gerlicher AMV, Tüscher O, Kalisch R, 2018. Dopamine-dependent prefrontal reactivations explain long-term benefit of fear extinction. Nat Commun 9, 4294. 10.1038/s41467-018-06785-y
    1. Gunduz-Cinar O, MacPherson KP, Cinar R, Gamble-George J, Sugden K, Williams B, Godlewski G, Ramikie TS, Gorka AX, Alapafuja SO, Nikas SP, Makriyannis A, Poulton R, Patel S, Hariri AR, Caspi A, Moffitt TE, Kunos G, Holmes A, 2013. Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry 18, 813–823. 10.1038/mp.2012.72
    1. Haaker J, Gaburro S, Sah A, Gartmann N, Lonsdorf TB, Meier K, Singewald N, Pape H-C, Morellini F, Kalisch R, 2013. Single dose of L-dopa makes extinction memories context-independent and prevents the return of fear. Proc. Natl. Acad. Sci. U.S.A 110, E2428–2436. 10.1073/pnas.1303061110
    1. Hayes AF, Rockwood NJ, 2017. Regression-based statistical mediation and moderation analysis in clinical research: Observations, recommendations, and implementation. Behav Res Ther 98, 39–57. 10.1016/j.brat.2016.11.001
    1. Heyman E, Gamelin F-X, Goekint M, Piscitelli F, Roelands B, Leclair E, Di Marzo V, Meeusen R, 2012Intense exercise increases circulating endocannabinoid and BDNF levels in humans--possible implications for reward and depression. Psychoneuroendocrinology 37, 844–851. 10.1016/j.psyneuen.2011.09.017
    1. Iverson KM, McLaughlin KA, Gerber MR, Dick A, Smith BN, Bell ME, Cook N, Mitchell KS,2013. Exposure to Interpersonal Violence and Its Associations With Psychiatric Morbidity in a U.S. National Sample: A Gender Comparison. Psychol Violence 3, 273–287. 10.1037/a0030956
    1. Jenniches I, Ternes S, Albayram O, Otte DM, Bach K, Bindila L, Michel K, Lutz B, Bilkei-Gorzo A, Zimmer A, 2016. Anxiety, stress, and fear response in mice with reduced endocannabinoid levels. Biol Psychiatry 79, 858–868. 10.1016/j.biopsych.2015.03.033
    1. 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. 10.1016/j.psyneuen.2014.11.002
    1. Kallies G, Rapp MA, Fydrich T, Fehm L, Tschorn M, Terán C, Schwefel M, Pietrek A, Henze R, Hellweg R, Ströhle A, Heinzel S, Heissel A, 2019. Serum brain-derived neurotrophic factor (BDNF) at rest and after acute aerobic exercise in major depressive disorder. Psychoneuroendocrinology 102, 212–215. 10.1016/j.psyneuen.2018.12.015
    1. Katona I, Freund TF, 2012. Multiple functions of endocannabinoid signaling in the brain. Annu. Rev. Neurosci 35, 529–558. 10.1146/annurev-neuro-062111-150420
    1. Kendler KS, Mohs RC, Davis KL, 1983. The effects of diet and physical activity on plasma homovanillic acid in normal human subjects. Psychiatry Res 8, 215–223. 10.1016/0165-1781(83)90065-3
    1. Kessler RC, Aguilar-Gaxiola S, Alonso J, Benjet C, Bromet EJ, Cardoso G, Degenhardt L, de Girolamo G, Dinolova RV, Ferry F, Florescu S, Gureje O, Haro JM, Huang Y, Karam EG, Kawakami N, Lee S, Lepine J-P, Levinson D, Navarro-Mateu F, Pennell B-E, Piazza M, Posada-Villa J, Scott KM, Stein DJ, Ten Have M, Torres Y, Viana MC, Petukhova MV, Sampson NA, Zaslavsky AM, Koenen KC, 2017. Trauma and PTSD in the WHO World Mental Health Surveys. Eur J Psychotraumatol 8, 1353383. 10.1080/20008198.2017.1353383
    1. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE, 2005. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62, 617–627. 10.1001/archpsyc.62.6.617
    1. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB, 1995. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 52, 1048–1060. 10.1001/archpsyc.1995.03950240066012
    1. Keyan D, Bryant RA, 2019. Acute exercise-induced enhancement of fear inhibition is moderated by BDNF Va166Met polymorphism. Transl Psychiatry 9, 131. 10.1038/s41398-019-0464-z
    1. Lafenêtre P, Chaouloff F, Marsicano G, 2007. The endocannabinoid system in the processing of anxiety and fear and how CB1 receptors may modulate fear extinction. Pharmacol. Res 56, 367–381. 10.1016/j.phrs.2007.09.006
    1. Lu Y, Christian K, Lu B, 2008. BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 89, 312–323. 10.1016/j.nlm.2007.08.018
    1. Lupica CR, Riegel AC, 2005. Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction. Neuropharmacology 48, 1105–1116. 10.1016/j.neuropharm.2005.03.016
    1. Lutz B, Marsicano G, Maldonado R, Hillard CJ, 2015. The endocannabinoid system in guarding against fear, anxiety and stress. Nat. Rev. Neurosci 16, 705–718. 10.1038/nrn4036
    1. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgänsberger W, Di Marzo V, Lutz B, 2002. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534. 10.1038/nature00839
    1. Mataix-Cols D, Fernández de la Cruz L, Monzani B, Rosenfield D, Andersson E, Pérez-Vigil A, Frumento P, de Kleine RA, Difede J, Dunlop BW, Farrell LJ, Geller D, Gerardi M, Guastella AJ, Hofmann SG, Hendriks G-J, Kushner MG, Lee FS, Lenze EJ, Levinson CA, McConnell H, Otto MW, Plag J, Pollack MH, Ressler KJ, Rodebaugh TL, Rothbaum BO, Scheeringa MS, Siewert-Siegmund A, Smits JAJ, Storch EA, Ströhle A, Tart CD, Tolin DF, van Minnen A, Waters AM, Weems CF, Wilhelm S, Wyka K, Davis M, Rück C, the DCS Anxiety Consortium, Altemus M, Anderson P, Cukor J, Finck C, Geffken GR, Golfels F, Goodman WK, Gutner C, Heyman F, Jovanovic T, Lewin AB, McNamara JP, Murphy TK, Norrholm S, Thuras P, 2017. D-Cycloserine augmentation of exposure-based cognitive behavior therapy for Anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data. JAMA Psychiatry 74, 501–510. 10.1001/jamapsychiatry.2016.3955
    1. Mayo LM, Asratian A, Lindé J, Holm L, Nätt D, Augier G, Stensson N, Vecchiarelli HA, Balsevich G, Aukema RJ, Ghafouri B, Spagnolo PA, Lee FS, Hill MN, Heilig M, 2020a. Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice. Mol. Psychiatry 25, 993–1005. 10.1038/s41380-018-0215-1
    1. Mayo LM, Asratian A, Lindé J, Morena M, Haataja R, Hammar V, Augier G, Hill MN, Heilig M, 2020b. Elevated anandamide, enhanced recall of fear extinction, and attenuated stress responses following inhibition of fatty acid amide hydrolase: A randomized, controlled experimental medicine trial. Biol. Psychiatry 87, 538–547. 10.1016/j.biopsych.2019.07.034
    1. McMorris T, Collard K, Corbett J, Dicks M, Swain JP, 2008. A test of the catecholamines hypothesis for an acute exercise-cognition interaction. Pharmacol Biochem Behav 89, 106–115. 10.1016/j.pbb.2007.11.007
    1. Meyer JD, Koltyn KF, Stegner AJ, Kim J-S, Cook DB, 2016. Relationships between serum BDNF and the antidepressant effect of acute exercise in depressed women. Psychoneuroendocrinology 74, 286–294. 10.1016/j.psyneuen.2016.09.022
    1. Morena M, Berardi A, Colucci P, Palmery M, Trezza V, Hill MN, Campolongo P, 2018. Enhancing Endocannabinoid neurotransmission augments the efficacy of extinction training and ameliorates traumatic stress-induced behavioral alterations in rats. Neuropsychopharmacology 43, 1284–1296. 10.1038/npp.2017.305
    1. Nachtigall EG, Furini CRG, Behling J. a. K., Farias CP, Izquierdo E, Myskiw J. de C, 2019. Facilitation of fear extinction by novelty is modulated by β-adrenergic and 5-HT1A serotoninergic receptors in hippocampus. Neurobiol Leam Mem 166, 107101. 10.1016/j.nlm.2019.107101
    1. Ney LJ, Akhurst J, Bruno R, Laing PAF, Matthews A, Felmingham KL, 2020. Dopamine, endocannabinoids and their interaction in fear extinction and negative affect in PTSD. Prog Neuropsychopharmacol Biol Psychiatry 105, 110118. 10.1016/j.pnpbp.2020.110118
    1. Notaras M, van den Buuse M, 2020. Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders. Mol Psychiatry 25, 2251–2274. 10.1038/s41380-019-0639-2
    1. Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ, 2010. Induction of fear extinction with hippocampal-infralimbic BDNF. Science 328, 1288–1290. 10.1126/science.1186909
    1. Powers MB, Medina JL, Burns S, Kauffman BY, Monfils M, Asmundson GJG, Diamond A, McIntyre C, Smits JAJ, 2015. Exercise augmentation of exposure therapy for PTSD: rationale and pilot efficacy data. Cogn Behav Ther 44, 314–327. 10.1080/16506073.2015.1012740
    1. Quirk GJ, Mueller D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology. 2008;33(1):56–72. 10.1038/sj.npp.1301555
    1. Rabinak CA, Angstadt M, Lyons M, Mori S, Milad MR, Liberzon I, Phan KL, 2014. Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans. Neurobiol Learn Mem 113, 125–134. 10.1016/j.nlm.2013.09.009
    1. Rabinak CA, Blanchette A, Zabik NL, Peters C, Marusak HA, Iadipaolo A, Elrahal F, 2020. Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study. Psychopharmacology (Berl) 237, 1813–1826. 10.1007/s00213-020-05499-8
    1. Resick PA, Nishith P, Weaver TL, Astin MC, Feuer CA, 2002. A comparison of cognitive-processing therapy with prolonged exposure and a waiting condition for the treatment of chronic posttraumatic stress disorder in female rape victims. J Consult Clin Psychol 70, 867–879. 10.1037//0022-006x.70.4.867
    1. Resnick HS, Kilpatrick DG, Dansky BS, Saunders BE, Best CL, 1993. Prevalence of civilian trauma and posttraumatic stress disorder in a representative national sample of women. J Consult Clin Psychol 61, 984–991. 10.1037//0022-006x.61.6.984
    1. Rothbaum BO, Davis M, 2003. Applying learning principles to the treatment of post-trauma reactions. Ann N Y Acad Sci. 1008, 112–21.
    1. Roquet RF, Monfils M-H, 2018. Does exercise augment operant and Pavlovian extinction: A meta-analysis. J Psychiatr Res 96, 73–93. 10.1016/j.jpsychires.2017.09.018
    1. Schnurr PP, Friedman MJ, Engel CC, Foa EB, Shea MT, Chow BK, Resick PA, Thurston V, Orsillo SM, Haug R, Turner C, Bernardy N, 2007. Cognitive behavioral therapy for posttraumatic stress disorder in women: a randomized controlled trial. JAMA 297, 820–830. 10.1001/jama.297.8.820
    1. Scott KM, Koenen KC, King A, Petukhova MV, Alonso J, Bromet EJ, Bruffaerts R, Bunting B, de Jonge P, Haro JM, Karam EG, Lee S, Medina-Mora ME, Navarro-Mateu F, Sampson NA, Shahly V, Stein DJ, Torres Y, Zaslavsky AM, Kessler RC, 2018. Post-traumatic stress disorder associated with sexual assault among women in the WHO World Mental Health Surveys. Psychol Med 48, 155–167. 10.1017/S0033291717001593
    1. Sherin JE, Nemeroff CB, 2011. Post-traumatic stress disorder: the neurobiological impact of psychological trauma. Dialogues Clin Neurosci 13, 263–278. 10.31887/DCNS.2011.13.2/jsherin
    1. Shrout PE, Bolger N, 2002. Mediation in experimental and nonexperimental studies: new procedures and recommendations. Psychol Methods 7, 422–445. 10.1037/1082-989X.7.4.422
    1. Tanner MK, Hake HS, Bouchet CA, Greenwood BN, 2018. Running from fear: exercise modulation of fear extinction. Neurobiol Learn Mem 151, 28–34. 10.1016/j.nlm.2018.03.021
    1. Torrisi SA, Leggio GM, Drago F, Salomone S, 2019. Therapeutic challenges of post-traumatic stress disorder: focus on the dopaminergic system. Front Pharmacol 10, 404. 10.3389/fphar.2019.00404
    1. Zhao L, Yeh MF-W, Fevine ES, 2015. Role for endogenous BDNF in endocannabinoid-mediated long-term depression at neocortical inhibitory synapses. eNeuro 2. 10.1523/ENEURO.0029-14.2015
    1. Zoellner LA, Telch M, Foa EB, Farach FJ, McLean CP, Gallop R, Bluett EJ, Cobb A, Gonzalez-Lima F, 2017. Enhancing extinction learning in posttraumatic stress disorder with brief daily imaginal exposure and methylene blue: a randomized controlled trial. J Clin Psychiatry 78, e782–e789. 10.4088/JCP.16m10936

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