Abstract
Rationale and objectives
Post-traumatic stress disorder (PTSD) is characterized by poor adaptation to a traumatic experience and disturbances in fear memory regulation, and currently lacks effective medication. Cannabidiol is a main constituent of Cannabis sativa; it has no psychotomimetic effects and has been implicated in modulating fear learning in mammals. Using a mouse PTSD model, we investigated the effects of CBD on PTSD-like behaviors and the modulation of trauma-related fear memory, a crucial process leading to core symptoms of PTSD.
Methods
We applied the modified pre-shock model to evaluated PTSD-like behaviors from days 3 to 26. The measures included the freezing time to the conditioned context, open field test, elevated plus maze test, and social interaction test. CBD and sertraline were administered at different stages of fear memory.
Results
CBD (10 mg/kg, i.p.) administration alleviated main PTSD-like symptoms in the mouse pre-shock model by attenuating trauma-related fear memory and anxiety-like behavior, and increasing social interaction behavior. The effects of CBD were apparent irrespective of whether it was administered before, during, or after re-exposure to the aversive context. However, sertraline (15 mg/kg, p.o.) was only effective when administered before the behavioral test. CBD also reduced the consolidation, retrieval, and reconsolidation of trauma-related fear memory, whereas sertraline only reduced fear-memory retrieval.
Conclusion
CBD produced anti-PTSD-like actions in mice and disrupted trauma-related fear memory by interfering with multiple aspects of fear memory processing. These findings indicate that CBD may be a promising candidate for treating PTSD.
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References
Ali RM, Al Kury LT, Yang KH, Qureshi A, Rajesh M, Galadari S, Shuba YM, Howarth FC, Oz M (2015) Effects of cannabidiol on contractions and calcium signaling in rat ventricular myocytes. Cell Calcium 57:290–299. https://doi.org/10.1016/j.ceca.2015.02.001
Anagnostaras SG, Wood SC, Shuman T, Cai DJ, Leduc AD, Zurn KR, Zurn JB, Sage JR, Herrera GM (2010) Automated assessment of pavlovian conditioned freezing and shock reactivity in mice using the video freeze system. Front Behav Neurosci 4https://doi.org/10.3389/fnbeh.2010.00158
Baldwin DS, Anderson IM, Nutt DJ, Allgulander C, Bandelow B, den Boer JA, Christmas DM, Davies S, Fineberg N, Lidbetter N, Malizia A, McCrone P, Nabarro D, O’Neill C, Scott J, van der Wee N, Wittchen HU (2014) Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol 28:403–439. https://doi.org/10.1177/0269881114525674
Bentefour Y, Rakibi Y, Bennis M, Ba-M’hamed S, Garcia R (2016) Paroxetine treatment, following behavioral suppression of PTSD-like symptoms in mice, prevents relapse by activating the infralimbic cortex. Eur Neuropsychopharmacol 26:195–207. https://doi.org/10.1016/j.euroneuro.2015.12.021
Betthauser K, Pilz J, Vollmer LE (2015) Use and effects of cannabinoids in military veterans with posttraumatic stress disorder. Am J Health Syst Pharm 72:1279–1284. https://doi.org/10.2146/ajhp140523
Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134:845–852. https://doi.org/10.1038/sj.bjp.0704327
Bonn-Miller MO, Vujanovic AA, Feldner MT, Bernstein A, Zvolensky MJ (2007) Posttraumatic stress symptom severity predicts marijuana use coping motives among traumatic event-exposed marijuana users. J Trauma Stress 20:577–586. https://doi.org/10.1002/jts.20243
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. https://doi.org/10.1001/archpsyc.55.7.626
Briscione MA, Michopoulos V, Jovanovic T, Norrholm SD (2017) Neuroendocrine underpinnings of increased risk for posttraumatic stress disorder in women. Vitam Horm 103:53–83. https://doi.org/10.1016/bs.vh.2016.08.003
Campos AC, Ferreira FR, Guimarães FS (2012) Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors. J Psychiatr Res 46:1501–1510. https://doi.org/10.1016/j.jpsychires.2012.08.012
Carrier EJ, Auchampach JA, Hillard CJ (2006) Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A 103:7895–7900. https://doi.org/10.1073/pnas.0511232103
Das RK, Kamboj SK, Ramadas M, Yogan K, Gupta V, Redman E, Curran HV, Morgan CJ (2013) Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology 226:781–792. https://doi.org/10.1007/s00213-012-2955-y
Davidson JR, Rothbaum BO, van der Kolk BA, Sikes CR, Farfel GM (2001) Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Arch Gen Psychiatry 58:485–492. https://doi.org/10.1001/archpsyc.58.5.485
Do-Monte FH, Manzano-Nieves G, Quiñones-Laracuente K, Ramos-Medina L, Quirk GJ (2015) Revisiting the role of infralimbic cortex in fear extinction with optogenetics. J Neurosci 35:3607–3615. https://doi.org/10.1523/JNEUROSCI.3137-14.2015
ElBatsh MM, Assareh N, Marsden CA, Kendall DA (2012) Anxiogenic-like effects of chronic cannabidiol administration in rats. Psychopharmacology 221:239–247. https://doi.org/10.1007/s00213-011-2566-z
El-Talatini MR, Taylor AH, Konje JC (2010) The relationship between plasma levels of the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle. Fertil Steril 93:1989–1996. https://doi.org/10.1016/j.fertnstert.2008.12.033
Evans AT, Formukong E, Evans FJ (1987) Activation of phospholipase A2 by cannabinoids. Lack of correlation with CNS effects. FEBS Lett 211:119–122. https://doi.org/10.1016/0014-5793(87)81420-5
Fanselow MS (1980) Conditioned and unconditional components of post-shock freezing. Pavlov J Biol Sci 15:177–182. https://doi.org/10.1007/bf03001163
Fesler FA (1991) Valproate in combat-related posttraumatic stress disorder. J Clin Psychiatry 52:361–364
Fineberg NA, Haddad PM, Carpenter L, Gannon B, Sharpe R, Young AH, Joyce E, Rowe J, Wellsted D, Nutt DJ, Sahakian BJ (2013) The size, burden and cost of disorders of the brain in the UK. J Psychopharmacol 27:761–770. https://doi.org/10.1177/0269881113495118
Ford N (1996) The use of anticonvulsants in posttraumatic stress disorder: case study and overview. J Trauma Stress 9:857–863. https://doi.org/10.1007/bf02104107
Forster PL, Schoenfeld FB, Marmar CR, Lang AJ (1995) Lithium for irritability in post-traumatic stress disorder. J Trauma Stress 8:143–149. https://doi.org/10.1007/bf02105412
Ganon-Elazar E, Akirav I (2012) Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress. Neuropsychopharmacology 37:456–466. https://doi.org/10.1038/npp.2011.204
García-Gutiérrez MS, Navarrete F, Gasparyan A, Austrich-Olivares A, Sala F, Manzanares J (2020) Cannabidiol: a potential new alternative for the treatment of anxiety, depression, and psychotic disorders. Biomolecules 10https://doi.org/10.3390/biom10111575
Gasparyan A, Navarrete F, Manzanares J (2021) Cannabidiol and sertraline regulate behavioral and brain gene expression alterations in an animal model of PTSD. Front Pharmacol 12:694510. https://doi.org/10.3389/fphar.2021.694510
Ghovanloo MR, Shuart NG, Mezeyova J, Dean RA, Ruben PC, Goodchild SJ (2018) Inhibitory effects of cannabidiol on voltage-dependent sodium currents. J Biol Chem 293:16546–16558. https://doi.org/10.1074/jbc.RA118.004929
Gonca E, Darıcı F (2015) The effect of cannabidiol on ischemia/reperfusion-induced ventricular arrhythmias: the role of adenosine A1 receptors. J Cardiovasc Pharmacol Ther 20:76–83. https://doi.org/10.1177/1074248414532013
González S, Bisogno T, Wenger T, Manzanares J, Milone A, Berrendero F, Di Marzo V, Ramos JA, Fernández-Ruiz JJ (2000) Sex steroid influence on cannabinoid CB(1) receptor mRNA and endocannabinoid levels in the anterior pituitary gland. Biochem Biophys Res Commun 270:260–266. https://doi.org/10.1006/bbrc.2000.2406
Graham B, Garcia NM, Bergman HE, Feeny NC, Zoellner LA (2020) Prolonged exposure and sertraline treatments for posttraumatic stress disorder also improve multiple indicators of social functioning. J Trauma Stress. https://doi.org/10.1002/jts.22570
Guimarães FS, Chiaretti TM, Graeff FG, Zuardi AW (1990) Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology 100:558–559. https://doi.org/10.1007/bf02244012
Hapke U, Schumann A, Rumpf HJ, John U, Meyer C (2006) Post-traumatic stress disorder: the role of trauma, pre-existing psychiatric disorders, and gender. Eur Arch Psychiatry Clin Neurosci 256:299–306. https://doi.org/10.1007/s00406-006-0654-6
Herrmann L, Ionescu IA, Henes K, Golub Y, Wang NX, Buell DR, Holsboer F, Wotjak CT, Schmidt U (2012) Long-lasting hippocampal synaptic protein loss in a mouse model of posttraumatic stress disorder. PLoS ONE 7:e42603. https://doi.org/10.1371/journal.pone.0042603
Hien DA, Levin FR, Ruglass LM, Lopez-Castro T, Papini S, Hu MC, Cohen LR, Herron A (2015) Combining seeking safety with sertraline for PTSD and alcohol use disorders: a randomized controlled trial. J Consult Clin Psychol 83:359–369. https://doi.org/10.1037/a0038719
Hillard CJ (2014) Stress regulates endocannabinoid-CB1 receptor signaling. Semin Immunol 26:380–388. https://doi.org/10.1016/j.smim.2014.04.001
Hiltunen AJ, Jarbe TU, Wangdahl K (1988) Cannabinol and cannabidiol in combination: temperature, open-field activity, and vocalization. Pharmacol Biochem Behav 30:675–678. https://doi.org/10.1016/0091-3057(88)90082-2
Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30:515–527. https://doi.org/10.1016/j.tips.2009.07.006
Kasten CR, Zhang Y, Boehm SL 2nd (2019) Acute cannabinoids produce robust anxiety-like and locomotor effects in mice, but long-term consequences are age- and sex-dependent. Front Behav Neurosci 13:32. https://doi.org/10.3389/fnbeh.2019.00032
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. https://doi.org/10.1001/archpsyc.1995.03950240066012
Kilpatrick DG, Resnick HS, Milanak ME, Miller MW, Keyes KM, Friedman MJ (2013) National estimates of exposure to traumatic events and PTSD prevalence using DSM-IV and DSM-5 criteria. J Trauma Stress 26:537–547. https://doi.org/10.1002/jts.21848
Koenen KC, Ratanatharathorn A, Ng L, McLaughlin KA, Bromet EJ, Stein DJ, Karam EG, Meron Ruscio A, Benjet C, Scott K, Atwoli L, Petukhova M, Lim CCW, Aguilar-Gaxiola S, Al-Hamzawi A, Alonso J, Bunting B, Ciutan M, de Girolamo G, Degenhardt L, Gureje O, Haro JM, Huang Y, Kawakami N, Lee S, Navarro-Mateu F, Pennell BE, Piazza M, Sampson N, Ten Have M, Torres Y, Viana MC, Williams D, Xavier M, Kessler RC (2017) Posttraumatic stress disorder in the World Mental Health Surveys. Psychol Med 47:2260–2274. https://doi.org/10.1017/S0033291717000708
Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM (2015) Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 172:4790–4805. https://doi.org/10.1111/bph.13250
Lemos JI, Resstel LB, Guimarães FS (2010) Involvement of the prelimbic prefrontal cortex on cannabidiol-induced attenuation of contextual conditioned fear in rats. Behav Brain Res 207:105–111. https://doi.org/10.1016/j.bbr.2009.09.045
Levin R, Almeida V, Peres FF, Calzavara MB, da Silva ND, Suiama MA, Niigaki ST, Zuardi AW, Hallak JE, Crippa JA, Abilio VC (2012) Antipsychotic profile of cannabidiol and rimonabant in an animal model of emotional context processing in schizophrenia. Curr Pharm Des 18:4960–4965. https://doi.org/10.2174/138161212802884735
Li S, Liao Y, Dong Y, Li X, Li J, Cheng Y, Cheng J, Yuan Z (2021) Microglial deletion and inhibition alleviate behavior of post-traumatic stress disorder in mice. J Neuroinflammation 18:7. https://doi.org/10.1186/s12974-020-02069-9
Li S, Murakami Y, Wang M, Maeda K, Matsumoto K (2006) The effects of chronic valproate and diazepam in a mouse model of posttraumatic stress disorder. Pharmacol Biochem Behav 85:324–331. https://doi.org/10.1016/j.pbb.2006.08.015
Lipper S, Davidson JR, Grady TA, Edinger JD, Hammett EB, Mahorney SL, Cavenar JO Jr (1986) Preliminary study of carbamazepine in post-traumatic stress disorder. Psychosomatics 27:849–854. https://doi.org/10.1016/s0033-3182(86)72590-5
Liu WG, Zhang LM, Yao JQ, Yin YY, Zhang XY, Li YF, Cao JB (2021) Anti-PTSD effects of hypidone hydrochloride (YL-0919): a novel combined selective 5-HT reuptake inhibitor/5-HT1A receptor partial agonist/5-HT6 receptor full agonist. Front Pharmacol 12:625547. https://doi.org/10.3389/fphar.2021.625547
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. https://doi.org/10.1038/nrn4036
Jiang R, Yamaori S, Okamoto Y, Yamamoto I, Watanabe K (2013) Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet 28:332–338. https://doi.org/10.2133/dmpk.dmpk-12-rg-129
Maier SF (1990) Role of fear in mediating shuttle escape learning deficit produced by inescapable shock. J Exp Psychol Anim Behav Process 16:137–149
Maren S (2001) Neurobiology of Pavlovian fear conditioning. Annu Rev Neurosci 24:897–931. https://doi.org/10.1146/annurev.neuro.24.1.897
Marshall RD, Pierce D (2000) Implications of recent findings in posttraumatic stress disorder and the role of pharmacotherapy. Harv Rev Psychiatry 7:247–256
Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534. https://doi.org/10.1038/nature00839
McAllister DE, McAllister WR (1967) Incubation of fear: an examination of the concept. J Exp Res Personality 2:180–190
Moreira FA, Wotjak CT (2010) Cannabinoids and anxiety. Curr Top Behav Neurosci 2:429–450. https://doi.org/10.1007/7854_2009_16
Nemeroff CB, Owens MJ (2004) Pharmacologic differences among the SSRIs: focus on monoamine transporters and the HPA axis. CNS Spectr 9:23–31. https://doi.org/10.1017/s1092852900025475
Oehen P, Traber R, Widmer V, Schnyder U (2013) A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). J Psychopharmacol 27:40–52. https://doi.org/10.1177/0269881112464827
Peng ZW, Xue YY, Wang HN, Wang HH, Xue F, Kuang F, Wang BR, Chen YC, Zhang LY, Tan QR (2012) Sertraline promotes hippocampus-derived neural stem cells differentiating into neurons but not glia and attenuates LPS-induced cellular damage. Prog Neuropsychopharmacol Biol Psychiatry 36:183–188. https://doi.org/10.1016/j.pnpbp.2011.08.014
Qiu ZK, He JL, Liu X, Zeng J, Chen JS, Nie H (2017) Anti-PTSD-like effects of albiflorin extracted from Radix paeoniae Alba. J Ethnopharmacol 198:324–330. https://doi.org/10.1016/j.jep.2016.12.028
Qiu ZK, Zhang LM, Zhao N, Chen HX, Zhang YZ, Liu YQ, Mi TY, Zhou WW, Li Y, Yang RF, Xu JP, Li YF (2013) Repeated administration of AC-5216, a ligand for the 18 kDa translocator protein, improves behavioral deficits in a mouse model of post-traumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 45:40–46. https://doi.org/10.1016/j.pnpbp.2013.04.010
Ratano P, Everitt BJ, Milton AL (2014) The CB1 receptor antagonist AM251 impairs reconsolidation of pavlovian fear memory in the rat basolateral amygdala. Neuropsychopharmacology 39:2529–2537. https://doi.org/10.1038/npp.2014.103
Rau V, DeCola JP, Fanselow MS (2005) Stress-induced enhancement of fear learning: an animal model of posttraumatic stress disorder. Neurosci Biobehav Rev 29:1207–1223. https://doi.org/10.1016/j.neubiorev.2005.04.010
Resstel LB, Joca SR, Moreira FA, Corrêa FM, Guimarães FS (2006) Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats. Behav Brain Res 172:294–298. https://doi.org/10.1016/j.bbr
Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037–1043. https://doi.org/10.1007/s11064-005-6978-1
Saiz-Rodriguez M, Belmonte C, Roman M, Ochoa D, Koller D, Talegon M, Ovejero-Benito MC, Lopez-Rodriguez R, Cabaleiro T, Abad-Santos F (2018) Effect of polymorphisms on the pharmacokinetics, pharmacodynamics and safety of sertraline in healthy volunteers. Basic Clin Pharmacol Toxicol 122:501–511. https://doi.org/10.1111/bcpt.12938
Seeman P (2016) Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose. Transl Psychiatry 6:e920. https://doi.org/10.1038/tp.2016.195
Siegmund A, Wotjak CT (2007) A mouse model of posttraumatic stress disorder that distinguishes between conditioned and sensitised fear. J Psychiatr Res 41:848–860. https://doi.org/10.1016/j.jpsychires.2006.07.017
Sitges M, Chiu LM, Reed RC (2016) Effects of levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, oxcarbazepine, topiramate, vinpocetine and sertraline on presynaptic hippocampal Na(+) and Ca(2+) channels permeability. Neurochem Res 41:758–769. https://doi.org/10.1007/s11064-015-1749-0
Song C, Stevenson CW, Guimaraes FS, Lee JL (2016) Bidirectional effects of cannabidiol on contextual fear memory extinction. Front Pharmacol 7:493. https://doi.org/10.3389/fphar.2016.00493
Song D, Ge Y, Chen Z, Shang C, Guo Y, Zhao T, Li Y, Wu N, Song R, Li J (2018) Role of dopamine D3 receptor in alleviating behavioural deficits in animal models of post-traumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 84:190–200. https://doi.org/10.1016/j.pnpbp.2018.03.001
Steenkamp MM, Litz BT, Hoge CW, Marmar CR (2015) Psychotherapy for military-related PTSD: A Review of Randomized Clinical Trials. JAMA 314:489–500. https://doi.org/10.1001/jama.2015.8370
Stern CA, Gazarini L, Takahashi RN, Guimaraes FS, Bertoglio LJ (2012) On disruption of fear memory by reconsolidation blockade: evidence from cannabidiol treatment. Neuropsychopharmacology 37:2132–2142. https://doi.org/10.1038/npp.2012.63
Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150:613–623. https://doi.org/10.1038/sj.bjp.0707133
Uhernik AL, Montoya ZT, Balkissoon CD, Smith JP (2018) Learning and memory is modulated by cannabidiol when administered during trace fear-conditioning. Neurobiol Learn Mem 149:68–76. https://doi.org/10.1016/j.nlm.2018.02.009
Usami N, Yamamoto I, Watanabe K (2008) Generation of reactive oxygen species during mouse hepatic microsomal metabolism of cannabidiol and cannabidiol hydroxy-quinone. Life Sci 83:717–724. https://doi.org/10.1016/j.lfs.2008.09.011
Valvassori SS, Bavaresco DV, Scaini G, Varela RB, Streck EL, Chagas MH, Hallak JE, Zuardi AW, Crippa JA, Quevedo J (2013) Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain. Braz J Psychiatry 35(4):380–386. https://doi.org/10.1590/1516-4446-2012-0886
Waleh NS, Cravatt BF, Apte-Deshpande A, Terao A, Kilduff TS (2002) Transcriptional regulation of the mouse fatty acid amide hydrolase gene. Gene 291:203–210. https://doi.org/10.1016/s0378-1119(02)00598-x
Wilson CB, McLaughlin LD, Ebenezer PJ, Nair AR, Francis J (2014) Valproic acid effects in the hippocampus and prefrontal cortex in an animal model of post-traumatic stress disorder. Behav Brain Res 268:72–80. https://doi.org/10.1016/j.bbr.2014.03.029
Xu JN, Chen LF, Su J, Liu ZL, Chen J, Lin QF, Mao WD, Gao ZW, Shen D (2018) The anxiolytic-like effects of estazolam on a PTSD animal model. Psychiatry Res 269:529–535. https://doi.org/10.1016/j.psychres.2018.08.118
Yau JOY, McNally GP (2018) Brain mechanisms controlling Pavlovian fear conditioning. J Exp Psychol Anim Learn Cogn 44:341–357. https://doi.org/10.1037/xan0000181
Zanelati TV, Biojone C, Moreira FA, Guimaraes FS, Joca SR (2010) Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol 159:122–128. https://doi.org/10.1111/j.1476-5381.2009.00521.x
Zhang LM, Yao JZ, Li Y, Li K, Chen HX, Zhang YZ, Li YF (2012) Anxiolytic effects of flavonoids in animal models of posttraumatic stress disorder. Evid Based Complement Alternat Med 2012: 623753https://doi.org/10.1155/2012/623753
Zhang LM, Zhou WW, Ji YJ, Li Y, Zhao N, Chen HX, Xue R, Mei XG, Zhang YZ, Wang HL, Li YF (2015) Anxiolytic effects of ketamine in animal models of posttraumatic stress disorder. Psychopharmacology 232:663–672. https://doi.org/10.1007/s00213-014-3697-9
Zhang XY, Wei W, Zhang YZ, Fu Q, Mi WD, Zhang LM, Li YF (2018) The 18 kDa translocator protein (TSPO) overexpression in hippocampal dentate gyrus elicits anxiolytic-like effects in a mouse model of post-traumatic stress disorder. Front Pharmacol 9:1364. https://doi.org/10.3389/fphar.2018.01364
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We thank Drs. Yunfeng Li and Liming Zhang at the Beijing Institute of Pharmacology and Toxicology for their insightful discussions.
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This work was supported by the Beijing Institute of Pharmacology and Toxicology.
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X.H. and J.L. designed the experiments; N.W. and J.L. supervised the experiments; X.H., X.K.S., and K.D.S. performed the behavioral experiments; H.Y.G., X.K.S., K. D.S., B.G.X, and X.H analyzed the data and prepared the figures; and X.H. and N.W. wrote the paper with contributions from all the other coauthors.
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Xiao Han and Xiankui Song contributed equally.
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Han, X., Song, X., Song, D. et al. Comparison between cannabidiol and sertraline for the modulation of post-traumatic stress disorder-like behaviors and fear memory in mice. Psychopharmacology 239, 1605–1620 (2022). https://doi.org/10.1007/s00213-022-06132-6
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DOI: https://doi.org/10.1007/s00213-022-06132-6