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Effects of a psychedelic 5-HT2A receptor agonist on anxiety-related behavior and fear processing in mice

Abstract

Psychedelic-assisted psychotherapy gained considerable interest as a novel treatment strategy for fear-related mental disorders but the underlying mechanism remains poorly understood. The serotonin 2A (5-HT2A) receptor is a key target underlying the effects of psychedelics on emotional arousal but its role in fear processing remains controversial. Using the psychedelic 5-HT2A/5-HT2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and 5-HT2A receptor knockout (KO) mice we investigated the effect of 5-HT2A receptor activation on emotional processing. We show that DOI administration did not impair performance in a spontaneous alternation task but reduced anxiety-like avoidance behavior in the elevated plus maze and elevated zero maze tasks. Moreover, we found that DOI did not block memory recall but diminished fear expression in a passive avoidance task. Likewise, DOI administration reduced fear expression in an auditory fear conditioning paradigm, while it did not affect retention of fear extinction when administered prior to extinction learning. The effect of DOI on fear expression was abolished in 5-HT2A receptor KO mice. Administration of DOI induced a significant increase of c-Fos expression in specific amygdalar nuclei. Moreover, local infusion of the 5-HT2A receptor antagonist M100907 into the amygdala reversed the effect of systemic administration of DOI on fear expression while local administration of DOI into the amygdala was sufficient to suppress fear expression. Our data demonstrate that activation of 5-HT2A receptors in the amygdala suppresses fear expression but provide no evidence for an effect on retention of fear extinction.

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Fig. 1: Effects of DOI on exploratory activity, innate and conditioned anxiety-like avoidance behavior.
Fig. 2: Effects of DOI on auditory fear extinction.
Fig. 3: Effects of DOI on neuronal activity during fear memory recall.
Fig. 4: Brain region-specific role of 5-HT2A receptors in the effects of DOI on freezing during fear memory recall.

References

  1. Battle DE. Diagnostic and statistical manual of mental disorders (DSM). Codas. 2013;25:191–2.

    Article  PubMed  Google Scholar 

  2. Shalev A, Liberzon I, Marmar C. Post-traumatic stress disorder. N Engl J Med. 2017;376:2459–69.

    Article  PubMed  Google Scholar 

  3. Maria M, Steenkamp P. Psychotherapy for military-Related PTSD: a review of randomized clinical trials. JAMA. 2015;314:489–500.

    Article  CAS  Google Scholar 

  4. Lee DJ, Schnitzlein CW, Wolf JP, Vythilingam M, Rasmusson AM, Hoge CW. Psychotherapy versus pharmacotherapy for posttraumatic stress disorder: systemic review and meta-analyses to determine first-line treatments. Depress Anxiety. 2016;33:792–806.

    Article  CAS  PubMed  Google Scholar 

  5. Hoskins M, Pearce J, Bethell A, Dankova L, Barbui C, Tol WA, et al. Pharmacotherapy for post-traumatic stress disorder: Systematic review and meta-analysis. Br J Psychiatry. 2015;206:93–100.

    Article  PubMed  Google Scholar 

  6. Bradley R, Greene J, Russ E, Dutra L, Westen D. A multidimensional meta-analysis of psychotherapy for PTSD. Am J Psychiatry. 2005;162:214–27.

    Article  PubMed  Google Scholar 

  7. Cipriani A, Williams T, Nikolakopoulou A, Salanti G, Chaimani A, Ipser J, et al. Comparative efficacy and acceptability of pharmacological treatments for post-traumatic stress disorder in adults: a network meta-analysis. Psychol Med. 2018;48:1975–84.

    Article  PubMed  Google Scholar 

  8. Milad MR, Quirk GJ. Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol. 2012;63:129.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Singewald N, Schmuckermair C, Whittle N, Holmes A, Ressler KJ. Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. Pharm Ther. 2015;149:150–90.

    Article  CAS  Google Scholar 

  10. Sartori SB, Singewald N. Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders. Pharm Ther. 2019;204:107402.

    Article  CAS  Google Scholar 

  11. Sessa B. Turn on and tune in to evidence-based psychedelic research. Lancet Psychiatry. 2015;2:10–2.

    Article  PubMed  Google Scholar 

  12. Mithoefer MC, Grob CS, Brewerton TD. Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. Lancet. Psychiatry. 2016;3:481–8.

    PubMed  Google Scholar 

  13. Kyzar EJ, Nichols CD, Gainetdinov RR, Nichols DE, Kalueff AV. Psychedelic drugs in biomedicine. Trends Pharm Sci. 2017;38:992–1005.

    Article  CAS  PubMed  Google Scholar 

  14. Reiff CM, Richman EE, Nemeroff CB, Carpenter LL, Widge AS, Rodriguez CI, et al. Psychedelics and psychedelic-assisted psychotherapy. Am J Psychiatry. 2020;177:391–410.

    Article  PubMed  Google Scholar 

  15. Krediet E, Bostoen T, Breeksema J, van Schagen A, Passie T, Vermetten E. Reviewing the potential of psychedelics for the treatment of PTSD. Int J Neuropsychopharmacol. 2020;23:385–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Feduccia AA, Jerome L, Yazar-Klosinski B, Emerson A, Mithoefer MC, Doblin R. Breakthrough for trauma treatment: safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline. Front Psychiatry. 2019;10:650.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Mitchell JM, Bogenschutz M, Lilienstein A, Harrison C, Kleiman S, Parker-Guilbert K, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27:1025–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liechti ME, Baumann C, Gamma A, Vollenweider FX. Acute psychological effects of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) are attenuated by the serotonin uptake inhibitor citalopram. Neuropsychopharmacology. 2000;22:513–21.

    Article  CAS  PubMed  Google Scholar 

  19. Mithoefer MC, Mithoefer AT, Feduccia AA, Jerome L, Wagner M, Wymer J, et al. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry. 2018;5:486–97.

    Article  PubMed  Google Scholar 

  20. Feduccia AA, Mithoefer MC. MDMA-assisted psychotherapy for PTSD: are memory reconsolidation and fear extinction underlying mechanisms? Prog Neuro-Psychopharmacol Biol Psychiatry. 2018;84:221–8.

    Article  CAS  Google Scholar 

  21. Young MB, Andero R, Ressler KJ, Howell LL. 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning. Transl Psychiatry. 2015;5:e634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Curry DW, Young MB, Tran AN, Daoud GE, Howell LL. Separating the agony from ecstasy: R(−)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice. Neuropharmacology. 2018;128:196–206.

    Article  CAS  PubMed  Google Scholar 

  23. Young MB, Norrholm SD, Khoury LM, Jovanovic T, Rauch SAM, Reiff CM, et al. Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA). Psychopharmacology. 2017;234:2883–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hake HS, Davis JKP, Wood RR, Tanner MK, Loetz EC, Sanchez A, et al. 3,4-methylenedioxymethamphetamine (MDMA) impairs the extinction and reconsolidation of fear memory in rats. Physiol Behav. 2019;199:343–50.

    Article  CAS  PubMed  Google Scholar 

  25. Holze F, Vizeli P, Müller F, Ley L, Duerig R, Varghese N, et al. Distinct acute effects of LSD, MDMA, and d-amphetamine in healthy subjects. Neuropsychopharmacology. 2020;45:462–71.

    Article  CAS  PubMed  Google Scholar 

  26. Han DD, Gu HH. Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol. 2006;6:6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Verrico CD, Lynch L, Fahey MA, Fryer A-K, Miller GM, Madras BK. MDMA-induced impairment in primates: antagonism by a selective norepinephrine or serotonin, but not by a dopamine/norepinephrine transport inhibitor. J Psychopharmacol. 2008;22:187–202.

    Article  CAS  PubMed  Google Scholar 

  28. Trigo JM, Renoir T, Lanfumey L, Hamon M, Lesch K-P, Robledo P, et al. 3,4-Methylenedioxymethamphetamine self-administration is abolished in serotonin transporter knockout mice. Biol Psychiatry. 2007;62:669–79.

    Article  CAS  PubMed  Google Scholar 

  29. Hagino Y, Takamatsu Y, Yamamoto H, Iwamura T, Murphy DL, Uhl GR, et al. Effects of MDMA on extracellular dopamine and serotonin levels in mice lacking dopamine and/or serotonin transporters. Curr Neuropharmacol. 2011;9:91–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rickli A, Kopf S, Hoener MC, Liechti ME. Pharmacological profile of novel psychoactive benzofurans. Br J Pharmacol. 2015;172:3412–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Doly S, Valjent E, Setola V, Callebert J, Hervé D, Launay J-M, et al. Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro. J Neurosci 2008;28:2933–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. van Wel JHP, Kuypers KPC, Theunissen EL, Bosker WM, Bakker K, Ramaekers JG. Effects of acute MDMA intoxication on mood and impulsivity: role of the 5-HT2 and 5-HT1 receptors. PLoS One. 2012;7:e40187.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Kuypers KPC, de la Torre R, Farre M, Pizarro N, Xicota L, Ramaekers JG. MDMA-induced indifference to negative sounds is mediated by the 5-HT 2A receptor. Psychopharmacology. 2018;235:481–90.

    Article  CAS  PubMed  Google Scholar 

  34. Catlow BJ, Song S, Paredes DA, Kirstein CL, Sanchez-Ramos J. Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. Exp Brain Res. 2013;228:481–91.

    Article  CAS  PubMed  Google Scholar 

  35. Zhang G, Ásgeirsdóttir HN, Cohen SJ, Munchow AH, Barrera MP, Stackman RW. Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice. Neuropharmacology. 2013;64:403–13.

    Article  CAS  PubMed  Google Scholar 

  36. Cameron L, Benson CJ, Dunlap LE, Olson DE. Effects of N,N-dimethyltryptamine on rat behaviors relevant to anxiety and depression. ACS Chem Neurosci. 2018;9:1582–90.

    Article  CAS  PubMed  Google Scholar 

  37. Cameron L, Benson CJ, DeFelice BC, Fiehn O, Olson DE. Chronic, intermittent microdoses of the psychedelic N,N-dimethyltryptamine (DMT) produce positive effects on mood and anxiety in rodents. ACS Chem Neurosci. 2019;10:3261–70.

    Article  CAS  PubMed  Google Scholar 

  38. Winstanley CA, Chudasama Y, Dalley JW, Theobald DEH, Glennon JC, Robbins TW. Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats. Psychopharmacology. 2003;167:304–14.

    Article  CAS  PubMed  Google Scholar 

  39. Darmani NA, Shaddy J, Gerdes CF. Differential ontogenesis of three DOI-induced behaviors in mice. Physiol Behav. 1996;60:1495–1500.

    Article  CAS  PubMed  Google Scholar 

  40. Pierre A, Van Schuerbeek A, Allaoui W, Van Laere S, Singewald N, Van Eeckhaut A, et al. Effects of ghrelin receptor activation on forebrain dopamine release, conditioned fear and fear extinction in C57BL/6J mice. J Neurochem. 8;154:389–403.

  41. Paxinos G, Franklin KB. Paxinos and Franklin’s the mouse brain in stereotaxic coordinates. Academic Press; 2019.

  42. De Bundel D, Schallier A, Loyens E, Fernando R, Miyashita H, Van Liefferinge J, et al. Loss of system xc− does not induce oxidative stress but decreases extracellular glutamate in hippocampus and influences spatial working memory and limbic seizure susceptibility. J Neurosci. 2011;31:5792–803.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Sarnyai Z, Sibille EL, Pavlides C, Fenster RJ, McEwen BS, Tóth M. Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin1A receptors. Proc Natl Acad Sci USA. 2000;97:14731–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zussy C, Gómez-Santacana X, Rovira X, De Bundel D, Ferrazzo S, Bosch D, et al. Dynamic modulation of inflammatory pain-related affective and sensory symptoms by optical control of amygdala metabotropic glutamate receptor 4. Mol Psychiatry. 2018;23:509–20.

    Article  CAS  PubMed  Google Scholar 

  45. Albertini G, Walrave L, Demuyser T, Massie A, De, Bundel D, et al. 6 Hz corneal kindling in mice triggers neurobehavioral comorbidities accompanied by relevant changes in c-Fos immunoreactivity throughout the brain. Epilepsia. 2018;59:67–78.

    Article  CAS  PubMed  Google Scholar 

  46. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82.

    Article  CAS  PubMed  Google Scholar 

  47. Wheeler A, Henriques R. Standard and super-resolution bioimaging data analysis: a primer. 312. Wiley Online Library; 2017.

  48. Maxwell SE, Delaney HD, Kelley K. Designing experiments and analyzing data: a model comparison perspective. Routledge; 2017.

  49. Canal CE, da Silva UBO, Gresch PJ, Watt EE, Sanders-Bush E, Airey DC. The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen. Psychopharmacology. 2010;209:163–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. De Bundel D, Gangarossa G, Biever A, Bonnefont X, Valjent E. Cognitive dysfunction, elevated anxiety, and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice. Front Behav Neurosci. 2013;7:152.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Puighermanal E, Castell L, Esteve-Codina A, Melser S, Kaganovsky K, Zussy C, et al. Functional and molecular heterogeneity of D2R neurons along dorsal-ventral axis in the striatum. Nat Commun. 2020;11:1957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bullitt E. Expression of C-fos-like protein as a marker for neuronal activity following noxious stimulation in the rat. J Comp Neurol. 1990;296:517–30.

    Article  CAS  PubMed  Google Scholar 

  53. Marek R, Sun Y, Sah P. Neural circuits for a top-down control of fear and extinction. Psychopharmacology. 2019;236:313–20.

    Article  CAS  PubMed  Google Scholar 

  54. Bocchio M, Fucsina G, Oikonomidis L, McHugh SB, Bannerman DM, Sharp T, et al. Increased serotonin transporter expression reduces fear and recruitment of parvalbumin interneurons of the amygdala. Neuropsychopharmacology. 2015;40:3015–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Jiang X, Xing G, Yang C, Verma A, Zhang L, Li H. Stress impairs 5-HT2A receptor-mediated serotonergic facilitation of GABA release in juvenile rat basolateral amygdala. Neuropsychopharmacology. 2009;34:410–23.

    Article  CAS  PubMed  Google Scholar 

  56. Ruotsalainen S, MacDonald E, Koivisto E, Stefanski R, Haapalinna A, Riekkinen P, et al. 5 -HT1A Receptor agonist (8-OH-DPAT) and 5-HT2 receptor agonist (DOI) disrupt the non-cognitive performance of rats in a working memory task. J Psychopharmacol. 1998;12:177–85.

    Article  CAS  PubMed  Google Scholar 

  57. Hjorth S, Magnusson T. The 5-HT 1A receptor agonist, 8-OH-DPAT, preferentially activates cell body 5-HT autoreceptors in rat brain in vivo. Naunyn-Schmiedebergs Arch Pharmacol. 1988;338:463–71.

    Article  CAS  PubMed  Google Scholar 

  58. Odland AU, Jessen L, Kristensen JL, Fitzpatrick CM, Andreasen JT. The 5-hydroxytryptamine 2A receptor agonists DOI and 25CN-NBOH decrease marble burying and reverse 8-OH-DPAT-induced deficit in spontaneous alternation. Neuropharmacology. 2021;183:107838.

    Article  CAS  PubMed  Google Scholar 

  59. Papakosta V-M, Kalogerakou S, Kontis D, Anyfandi E, Theochari E, Boulougouris V, et al. 5-HT2C receptor involvement in the control of persistence in the Reinforced Spatial Alternation animal model of obsessive–compulsive disorder. Behav Brain Res. 2013;243:176–83.

    Article  CAS  PubMed  Google Scholar 

  60. Hameleers R, Blokland A, Steinbusch HWM, Visser-Vandewalle V, Temel Y. Hypomobility after DOI administration can be reversed by subthalamic nucleus deep brain stimulation. Behav Brain Res. 2007;185:65–7.

    Article  CAS  PubMed  Google Scholar 

  61. Krebs-Thomson K, Geyer MA. Evidence for a functional interaction between 5-HT1A and 5-HT2 receptors in rats. Psychopharmacology. 1998;140:69–74.

    Article  CAS  PubMed  Google Scholar 

  62. Wing LL, Tapson GS, Geyer MA. 5HT-2 mediation of acute behavioral effects of hallucinogens in rats. Psychopharmacology. 1990;100:417–25.

    Article  CAS  PubMed  Google Scholar 

  63. Mittman SM, Geyer MA. Dissociation of multiple effects of acute LSD on exploratory behavior in rats by ritanserin and propranolol. Psychopharmacology. 1991;105:69–76.

    Article  CAS  PubMed  Google Scholar 

  64. Halberstadt AL, van der Heijden I, Ruderman MA, Risbrough VB, Gingrich JA, Geyer MA, et al. 5-HT2A and 5-HT2C receptors exert opposing effects on locomotor activity in mice. Neuropsychopharmacology. 2009;34:1958–67.

    Article  CAS  PubMed  Google Scholar 

  65. Onaivi ES, Bishop-Robinson C, Darmani NA, Sanders-Bush E. Behavioral effects of (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (DOI) in the elevated plus-maze test. Life Sci. 1995;57:2455–66.

    Article  CAS  PubMed  Google Scholar 

  66. Nic Dhonnchadha BÁ, Hascoët M, Jolliet P, Bourin M. Evidence for a 5-HT2A receptor mode of action in the anxiolytic-like properties of DOI in mice. Behav Brain Res. 2003;147:175–84.

    Article  CAS  PubMed  Google Scholar 

  67. Ripoll N, Hascoët M, Bourin M. Implication of 5-HT2A subtype receptors in DOI activity in the four-plates test-retest paradigm in mice. Behav Brain Res. 2006;166:131–9.

    Article  CAS  PubMed  Google Scholar 

  68. Lapin IP. Anxiogenic effect of phenylethylamine and amphetamine in the elevated plus-maze in mice and its attenuation by ethanol. Pharm Biochem Behav. 1993;44:241–3.

    Article  CAS  Google Scholar 

  69. Lin HQ, Burden PM, Christie MJ, Johnston GA. The anxiogenic-like and anxiolytic-like effects of MDMA on mice in the elevated plus-maze: a comparison with amphetamine. Pharm Biochem Behav. 1999;62:403–8.

    Article  CAS  Google Scholar 

  70. Biala G, Kruk M. Effects of co-administration of bupropion and nicotine or D-amphetamine on the elevated plus maze test in mice. J Pharm Pharmacol. 2009;61:493–502.

    Article  CAS  PubMed  Google Scholar 

  71. LeDoux J. The amygdala. Curr Biol. 2007;17:R868–74.

    Article  CAS  PubMed  Google Scholar 

  72. Maćkowiak M, Chocyk A, Fijał K, Czyrak A, Wedzony K. c-Fos proteins, induced by the serotonin receptor agonist DOI, are not expressed in 5-HT2A positive cortical neurons. Brain Res Mol Brain Res. 1999;71:358–63.

    Article  PubMed  Google Scholar 

  73. Martin DA, Nichols CD. Psychedelics recruit multiple cellular types and produce complex transcriptional responses within the brain. EBioMedicine. 2016;11:262–77.

    Article  PubMed  PubMed Central  Google Scholar 

  74. de Paula Soares V, Zangrossi H. Stimulation of 5-HT1A or 5-HT2A receptors in the ventrolateral periaqueductal gray causes anxiolytic-, but not panicolytic-like effect in rats. Behav Brain. 2009;197:178–85.

    Article  CAS  Google Scholar 

  75. Petit-Demoulière B, Massé F, Cogrel N, Hascoët M, Bourin M. Brain structures implicated in the four-plate test in naïve and experienced Swiss mice using injection of diazepam and the 5-HT2A agonist DOI. Behav Brain Res. 2009;204:200–5.

    Article  PubMed  CAS  Google Scholar 

  76. Hessel M, Pape H-C, Seidenbecher T. Stimulation of 5-HT receptors in anterodorsal BNST guides fear to predictable and unpredictable threat. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol. 2020;39:56–69.

    Article  CAS  Google Scholar 

  77. Gasser P, Kirchner K, Passie T. LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects. J Psychopharmacol. 2014;29:57–68.

    Article  PubMed  CAS  Google Scholar 

  78. Goldberg SB, Pace BT, Nicholas CR, Raison CL, Hutson PR. The experimental effects of psilocybin on symptoms of anxiety and depression: a meta-analysis. Psychiatry Res. 2020;284:112749.

    Article  CAS  PubMed  Google Scholar 

  79. Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30:1165–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 2016;30:1181–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Muttoni S, Ardissino M, John C. Classical psychedelics for the treatment of depression and anxiety: a systematic review. J Affect Disord. 2019;258:11–24.

    Article  PubMed  Google Scholar 

  82. Kraehenmann R, Schmidt A, Friston K, Preller KH, Seifritz E, Vollenweider FX. The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity. NeuroImage Clin. 2016;11:53–60.

    Article  PubMed  Google Scholar 

  83. Dolder PC, Schmid Y, Müller F, Borgwardt S, Liechti ME. LSD acutely impairs fear recognition and enhances emotional empathy and sociality. Neuropsychopharmacology. 2016;41:2638–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Risbrough VB, Brodkin JD, Geyer MA. GABA-A and 5-HT1A receptor agonists block expression of fear-potentiated startle in mice. Neuropsychopharmacology. 2003;28:654–63.

    Article  CAS  PubMed  Google Scholar 

  85. Zhao Y, Bijlsma EY, ter Heegde F, Verdouw MP, Garssen J, Newman-Tancredi A, et al. Activation of somatodendritic 5-HT 1A autoreceptors reduces the acquisition and expression of cued fear in the rat fear-potentiated startle test. Psychopharmacology. 2019;236:1171–85.

    Article  CAS  PubMed  Google Scholar 

  86. Wang C-C, Lin H-C, Chan Y-H, Gean P-W, Yang YK, Chen PS. 5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model. Int J Neuropsychopharmacol. 2013;16:2027–39.

    Article  CAS  PubMed  Google Scholar 

  87. Koseki H, Matsumoto M, Togashi H, Miura Y, Fukushima K, Yoshioka M. Alteration of synaptic transmission in the hippocampal-mPFC pathway during extinction trials of context-dependent fear memory in juvenile rat stress models. Synapse. 2009;63:805–13.

    Article  CAS  PubMed  Google Scholar 

  88. de la Fuente Revenga M, Zhu B, Guevara CA, Naler LB, Saunders JM, Zhou Z, et al. Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice. Cell Rep. 2021;37:109836.

    Article  PubMed  CAS  Google Scholar 

  89. Padich RA, McCloskey TC, Kehne JH. 5-HT modulation of auditory and visual sensorimotor gating: II. Effects of the 5-HT 2A antagonist MDL 100,907 on disruption of sound and light prepulse inhibition produced by 5-HT agonists in Wistar rats. Psychopharmacology. 1996;124:107–16.

    Article  CAS  PubMed  Google Scholar 

  90. Orejarena MJ, Lanfumey L, Maldonado R, Robledo P. Involvement of 5-HT2A receptors in MDMA reinforcement and cue-induced reinstatement of MDMA-seeking behaviour. Int J Neuropsychopharmacol. 2011;14:927–40.

    Article  CAS  PubMed  Google Scholar 

  91. Kehne JH, Ketteler HJ, McCloskey TC, Sullivan CK, Dudley MW, Schmidt CJ. Effects of the selective 5-HT2A receptor antagonist MDL 100,907 on MDMA-induced locomotor stimulation in rats. Neuropsychopharmacology. 1996;15:116–24.

    Article  CAS  PubMed  Google Scholar 

  92. Herin DV, Liu S, Ullrich T, Rice KC, Cunningham KA. Role of the serotonin 5-HT 2A receptor in the hyperlocomotive and hyperthermic effects of (+)-3,4-methylenedioxymethamphetamine. Psychopharmacology. 2005;178:505–13.

    Article  CAS  PubMed  Google Scholar 

  93. Pitts EG, Minerva AR, Chandler EB, Kohn JN, Logun MT, Sulima A, et al. 3,4-Methylenedioxymethamphetamine increases affiliative behaviors in squirrel monkeys in a serotonin 2A receptor-dependent manner. Neuropsychopharmacology. 2017;42:1962–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge the practical support of Wissal Allaoui, Gino De Smet, and Anke De Smet.

Funding

This work was supported by the Fund for Scientific Research Flanders (G023020N to DDB), by grants from CNRS, INSERM, University of Montpellier, iSITE MUSE and Fondation pour la Recherche Médicale (to PM, JB, and CB) and by INSERM, Fondation pour la Recherche Médicale (DEQ20160334919) and the French National Research Agency ANR (DOPAFEAR to EV).

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DDB., EV, and CB conceived the original idea. JB and PM contributed to conception of the study. DDB, EV, and BP designed the experiments. DDB, BP, SR, MS, and AVS carried out the experiments. DDB and BP analyzed the data. AP provided technical training and contributed to supervising the experiments. CB contributed essential materials. DDB and BP wrote the manuscript. All authors contributed to interpretation of the results and provided critical feedback on the manuscript.

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Correspondence to Dimitri De Bundel.

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Pędzich, B.D., Rubens, S., Sekssaoui, M. et al. Effects of a psychedelic 5-HT2A receptor agonist on anxiety-related behavior and fear processing in mice. Neuropsychopharmacol. 47, 1304–1314 (2022). https://doi.org/10.1038/s41386-022-01324-2

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