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Serotonin 2C receptors are also important in head-twitch responses in male mice

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Abstract

Rationale

Serotonergic psychedelics exert their effects via their high affinity for serotonin (5-HT) receptors, particularly through activating 5-HT2A receptors (5-HT2AR), employing the frontal cortex-dependent head-twitch response (HTR). Although universally believed to be so, studies have not yet fully ascertained whether 5-HT2AR activation is the sole initiator of these psychedelic effects. This is because not all 5-HT2AR agonists exhibit similar pharmacologic properties.

Objective

This study aims to identify and discriminate the roles of 5-HT2AR and 5-HT2CR in the HTR induced by Methallylescaline (MAL) and 4-Methyl-2,5,β-trimethoxyphenethylamine (BOD) in male mice. Also, an analysis of their potential neurotoxic properties was evaluated.

Methods

Male mice treated with MAL and BOD were evaluated in different behavioral paradigms targeting HTR and neurotoxicity effects. Drug affinity, pharmacological blocking, and molecular analysis were also conducted to support the behavioral findings. The HTR induced by DOI has been extensively characterized in male mice, making it a good positive control for this study, specifically for comparing the pharmacological effects of our test compounds.

Results

The activation of 5-HT2CR, alone or in concert with 5-HT2AR, produces a comparable degree of HTRs (at a dose of 1 mg·kg−1), with divergent 5-HT2CR- and 5-HT2AR-Gqα11-mediated signaling and enhanced neurotoxic properties (at a dose of 30 mg·kg−1) coupled with activated pro-inflammatory cytokines. These findings show these compounds’ potential psychedelic and neurotoxic effects in male mice.

Conclusion

These findings showed that while 5-HT2AR is the main initiator of HTR, the 5-HT2CR also has a distinct property that renders it effective in inducing HTR in male mice.

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Data availability

The data that support the findings of this study are original and available from the corresponding author upon reasonable request.

References

  • Abiero A, Botanas CJ, Custodio RJ, Sayson LV, Kim M, Lee HJ, Kim HJ, Lee KW, Jeong Y, Seo J-W (2020a) 4-MeO-PCP and 3-MeO-PCMo, new dissociative drugs, produce rewarding and reinforcing effects through activation of mesolimbic dopamine pathway and alteration of accumbal CREB, deltaFosB, and BDNF levels. Psychopharmacology 237:757–772

    Article  CAS  PubMed  Google Scholar 

  • Abiero A, Botanas CJ, Sayson LV, Custodio RJ, de la Peña JB, Kim M, Lee HJ, Seo J-W, Ryu IS, Chang CM (2019) 5-Methoxy-α-methyltryptamine (5-MeO-AMT), a tryptamine derivative, induces head-twitch responses in mice through the activation of serotonin receptor 2a in the prefrontal cortex. Behav Brain Res 359:828–835

    Article  CAS  PubMed  Google Scholar 

  • Abiero A, Custodio RJP, Botanas CJ, Ortiz DM, Sayson LV, Kim M, Lee HJ, Yoon S, Lee YS, Cheong JH (2021) 1-Phenylcyclohexan-1-amine hydrochloride (PCA HCl) alters mesolimbic dopamine system accompanied by neuroplastic changes: a neuropsychopharmacological evaluation in rodents. Neurochem Int 144:104962

    Article  CAS  PubMed  Google Scholar 

  • Abiero A, Ryu IS, Botanas CJ, Custodio RJP, Sayson LV, Kim M, Lee HJ, Kim HJ, Seo J-W, Cho MC (2020b) Four novel synthetic tryptamine analogs induce head-twitch responses and increase 5-HTR2a in the prefrontal cortex in mice. Biomol Ther 28:83

    Article  CAS  Google Scholar 

  • Adamaszek M, Khaw AV, Buck U, Andresen B, Thomasius R (2010) Evidence of neurotoxicity of ecstasy: sustained effects on electroencephalographic activity in polydrug users. PLoS One 5:e14097

    Article  PubMed  PubMed Central  Google Scholar 

  • Aghajanian G, Sprouse J, Sheldon P, Rasmussen K (1990) Electrophysiology of the central serotonin system: receptor subtypes and transducer mechanisms. Ann N Y Acad Sci 600:93–103

    Article  CAS  PubMed  Google Scholar 

  • Aghajanian GK, Marek GJ (1999) Serotonin and hallucinogens. Neuropsychopharmacology 21:16S-23S

    Article  CAS  PubMed  Google Scholar 

  • Ali SF, Newport GD, Scallet AC, Binienda Z, Ferguson SA, Bailey JR, Paule MG, Slikker W Jr (1993) Oral administration of 3, 4-methylenedioxymethamphetamine (MDMA) produces selective serotonergic depletion in the nonhuman primate. Neurotoxicol Teratol 15:91–96

    Article  CAS  PubMed  Google Scholar 

  • Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13:93–110

    Article  CAS  PubMed  Google Scholar 

  • Battaglia G, Yeh S, De Souza EB (1988) MDMA-induced neurotoxicity: parameters of degeneration and recovery of brain serotonin neurons. Pharmacol Biochem Behav 29:269–274

    Article  CAS  PubMed  Google Scholar 

  • Becher B, Spath S, Goverman J (2017) Cytokine networks in neuroinflammation. Nat Rev Immunol 17:49–59

    Article  CAS  PubMed  Google Scholar 

  • Benekareddy M, Nair AR, Dias BG, Suri D, Autry AE, Monteggia LM, Vaidya VA (2013) Induction of the plasticity-associated immediate early gene Arc by stress and hallucinogens: role of brain-derived neurotrophic factor. Int J Neuropsychopharmacol 16:405–415

    Article  CAS  PubMed  Google Scholar 

  • Benington F, Morin R, Clark LC (1954) Mescaline analogs. I. 2, 4, 6-trialkoxy-β-phenethylamines. J Org Chem 19:11–16

    Article  CAS  Google Scholar 

  • Berg KA, Clarke WP (2018) Making sense of pharmacology: inverse agonism and functional selectivity. Int J Neuropsychopharmacol 21:962–977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berg KA, Maayani S, Goldfarb J, Scaramellini C, Leff P, Clarke WP (1998) Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol Pharmacol 54:94–104

    Article  CAS  PubMed  Google Scholar 

  • Beyeler A, Ju A, Chagraoui A, Cuvelle L, Teixeira M, Di Giovanni G, De Deurwaerdère P (2021) Multiple facets of serotonergic modulation. Prog Brain Res 261:3–39

    Article  PubMed  Google Scholar 

  • Botanas CJ, Custodio RJP, Kim HJ, de la Pena JB, Sayson LV, Ortiz DM, Kim M, Lee HJ, Acharya S, Kim K-M (2021) R (−)-methoxetamine exerts rapid and sustained antidepressant effects and fewer behavioral side effects relative to S (+)-methoxetamine. Neuropharmacology 193:108619

    Article  CAS  PubMed  Google Scholar 

  • Botanas CJ, de la Peña JB, Custodio RJ, dela Peña IJ, Kim M, Woo T, Kim HJ, Kim HI, Cho MC, Lee YS (2017) Methoxetamine produces rapid and sustained antidepressant effects probably via glutamatergic and serotonergic mechanisms. Neuropharmacology 126:121-127

  • Botanas CJ, Yoon SS, de la Peña JB, dela Peña IJ, Kim M, Custodio RJ, Woo T, Seo J-W, Jang C-G, Yang JS (2018) A new synthetic drug 5-(2-aminopropyl) indole (5-IT) induces rewarding effects and increases dopamine D1 receptor and dopamine transporter mRNA levels. Behav Brain Res 341:122-128

  • Canal CE, Booth RG, Morgan D (2013) Support for 5-HT2C receptor functional selectivity in vivo utilizing structurally diverse, selective 5-HT2C receptor ligands and the 2, 5-dimethoxy-4-iodoamphetamine elicited head-twitch response model. Neuropharmacology 70:112–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Canal CE, Da Silva UBO, Gresch PJ, Watt EE, Sanders-Bush E, Airey DC (2010a) The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen. Psychopharmacology 209:163–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Canal CE, Morgan D (2012) Head-twitch response in rodents induced by the hallucinogen 2, 5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model. Drug Test Anal 4:556–576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Canal CE, Olaghere da Silva UB, Gresch PJ, Watt EE, Sanders-Bush E, Airey DC (2010b) The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen. Psychopharmacology 209:163–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao C, Barros-Álvarez X, Zhang S, Kim K, Dämgen MA, Panova O, Suomivuori C-M, Fay JF, Zhong X, Krumm BE (2022) Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD. Neuron 110:3154-3167.e7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Capela JP, Carmo H, Remião F, Bastos ML, Meisel A, Carvalho F (2009) Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview. Mol Neurobiol 39:210–271

    Article  CAS  PubMed  Google Scholar 

  • Cassels BK, Sáez-Briones P (2018) Dark classics in chemical neuroscience: mescaline. ACS Chem Neurosci 9:2448–2458

    Article  CAS  PubMed  Google Scholar 

  • Celada P, Puig MV, Artigas F (2013) Serotonin modulation of cortical neurons and networks. Front Integr Neurosci 7:25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chambers JJ, Kurrasch-Orbaugh DM, Nichols DE (2002) Translocation of the 5-alkoxy substituent of 2, 5-dialkoxyarylalkylamines to the 6-position: effects on 5-HT2A/2C receptor affinity. Bioorg Med Chem Lett 12:1997–1999

    Article  CAS  PubMed  Google Scholar 

  • Chang C-w, Poteet E, Schetz JA, Gümüş ZH, Weinstein H (2009) Towards a quantitative representation of the cell signaling mechanisms of hallucinogens: measurement and mathematical modeling of 5-HT1A and 5-HT2A receptor-mediated ERK1/2 activation. Neuropharmacology 56:213–225

    Article  CAS  PubMed  Google Scholar 

  • Cheng Y-C, Prusoff WH (1974) Mouse ascites sarcoma 180 deoxythymidine kinase. General properties and inhibition studies. Biochemistry 13:1179–1185

    Article  CAS  PubMed  Google Scholar 

  • Commins D, Vosmer G, Virus R, Woolverton W, Schuster C, Seiden L (1987) Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain. J Pharmacol Exp Ther 241:338–345

    CAS  PubMed  Google Scholar 

  • Cowen P, Sherwood AC (2013) The role of serotonin in cognitive function: evidence from recent studies and implications for understanding depression. J Psychopharmacol 27:575–583

    Article  PubMed  Google Scholar 

  • Cumming P, Scheidegger M, Dornbierer D, Palner M, Quednow BB, Martin-Soelch C (2021) Molecular and functional imaging studies of psychedelic drug action in animals and humans. Molecules 26:2451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Custodio RJP, Botanas CJ, de la Pena JB, dela Peña IJ, Kim M, Sayson LV, Abiero A, Ryoo ZY, Kim B-N, Kim HJ (2018) Overexpression of the thyroid hormone-responsive (THRSP) gene in the striatum leads to the development of inattentive-like phenotype in mice. Neuroscience 390:141-150

  • Custodio RJP, Botanas CJ, Yoon SS, De La Pena JB, dela Peña IJ, Kim M, Woo T, Seo J-W, Jang C-G, Kwon YH (2017) Evaluation of the abuse potential of novel amphetamine derivatives with modifications on the amine (NBNA) and phenyl (EDA, PMEA, 2-APN) sites. Biomol Ther 25:578

  • Custodio RJP, Hobloss Z, Myllys M, Hassan R, González D, Reinders J, Bornhorst J, Weishaupt A-K, Seddek A-l, Abbas T (2023a) Cognitive functions, neurotransmitter alterations, and hippocampal microstructural changes in mice caused by feeding on western diet. Cells 12:2331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Custodio RJP, Kim HJ, Kim J, Ortiz DM, Kim M, Buctot D, Sayson LV, Lee HJ, Kim B-N, Yi EC (2023b) Hippocampal dentate gyri proteomics reveals Wnt signaling involvement in the behavioral impairment in the THRSP-overexpressing ADHD mouse model. Commun Biol 6:55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Custodio RJP, Kim M, Sayson LV, Lee HJ, Ortiz DM, Kim B-N, Kim HJ, Cheong JH (2021) Low striatal T3 is implicated in inattention and memory impairment in an ADHD mouse model overexpressing thyroid hormone-responsive protein. Commun Biol 4:1101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Custodio RJP, Kim M, Sayson LV, Ortiz DM, Buctot D, Lee HJ, Cheong JH, Kim HJ (2022) Regulation of clock and clock-controlled genes during morphine reward and reinforcement: Involvement of the period 2 circadian clock. J Psychopharmacol 36:875–891

    Article  CAS  PubMed  Google Scholar 

  • Custodio RJP, Sayson LV, Botanas CJ, Abiero A, Kim M, Lee HJ, Ryu HW, Lee YS, Kim HJ, Cheong JH (2020a) Two newly-emerging substituted phenethylamines MAL and BOD induce differential psychopharmacological effects in rodents. J Psychopharmacol 34:1056–1067

    Article  CAS  PubMed  Google Scholar 

  • Custodio RJP, Sayson LV, Botanas CJ, Abiero A, You KY, Kim M, Lee HJ, Yoo SY, Lee KW, Lee YS (2020b) 25B-NBOMe, a novel N-2-methoxybenzyl-phenethylamine (NBOMe) derivative, may induce rewarding and reinforcing effects via a dopaminergic mechanism: Evidence of abuse potential. Addict Biol 25:e12850

    Article  CAS  PubMed  Google Scholar 

  • Dave KD, Harvey JA, Aloyo VJ (2002) A novel behavioral model that discriminates between 5-HT2A and 5-HT2C receptor activation. Pharmacol Biochem Behav 72:371–378

    Article  CAS  PubMed  Google Scholar 

  • de la Fuente RM, Jaster AM, McGinn J, Silva G, Saha S, González-Maeso J (2022) Tolerance and cross-tolerance among psychedelic and nonpsychedelic 5-HT2A receptor agonists in mice. ACS Chem Neurosci 13:2436–2448

    Article  Google Scholar 

  • De Vos CM, Mason NL, Kuypers KP (2021) Psychedelics and neuroplasticity: a systematic review unraveling the biological underpinnings of psychedelics. Front Psych 12:724606

    Article  Google Scholar 

  • dela Peña IJI, Botanas CJ, de la Peña JB, Custodio RJ, dela Peña I, Ryoo ZY, Kim B-N, Ryu JH, Kim HJ, Cheong JH (2019) The Atxn7-overexpressing mice showed hyperactivity and impulsivity which were ameliorated by atomoxetine treatment: a possible animal model of the hyperactive-impulsive phenotype of ADHD. Prog Neuro-Psychopharmacol Biol Psychiatr 88:311-319

  • Desouza LA, Benekareddy M, Fanibunda SE, Mohammad F, Janakiraman B, Ghai U, Gur T, Blendy JA, Vaidya VA (2021) The hallucinogenic serotonin2a receptor agonist, 2, 5-dimethoxy-4-iodoamphetamine, promotes camp response element binding protein-dependent gene expression of specific plasticity-associated genes in the rodent neocortex. Front Mol Neurosci 24(14)

  • Fantegrossi W, Woods J, Winger G (2004) Transient reinforcing effects of phenylisopropylamine and indolealkylamine hallucinogens in rhesus monkeys. Behav Pharmacol 15:149–157

    Article  CAS  PubMed  Google Scholar 

  • Fantegrossi WE, Murnane KS, Reissig CJ (2008) The behavioral pharmacology of hallucinogens. Biochem Pharmacol 75:17–33

    Article  CAS  PubMed  Google Scholar 

  • Fitzpatrick M (2014) Measuring cell fluorescence using ImageJ. The Open Lab Book

    Google Scholar 

  • Fletcher PJ, Sinyard J, Higgins GA (2006) The effects of the 5-HT 2C receptor antagonist SB242084 on locomotor activity induced by selective, or mixed, indirect serotonergic and dopaminergic agonists. Psychopharmacology 187:515–525

    Article  CAS  PubMed  Google Scholar 

  • Frankel PS, Cunningham KA (2002) The hallucinogen d-lysergic acid diethylamide (d-LSD) induces the immediate-early gene c-Fos in rat forebrain. Brain Res 958:251–260

    Article  CAS  PubMed  Google Scholar 

  • Franklin KB, Paxinos G (2008) The mouse brain in stereotaxic coordinates. Academic press, New York

    Google Scholar 

  • Garcia EE (2007) Unraveling the role of G-proteins in hallucinogenic drug action. Neuropharmacology 52:1671–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geyer M, Nichols D, Vollenweider F (2017) Serotonin-related psychedelic drugs. Reference Module in Neurosci and Biobehav Psychol. https://doi.org/10.1016/B978-0-12-809324-5.02392-0

    Article  Google Scholar 

  • Geyer MA, Vollenweider FX (2008) Serotonin research: contributions to understanding psychoses. Trends Pharmacol Sci 29:445–453

    Article  CAS  PubMed  Google Scholar 

  • Glennon R, Teitler M, Sanders-Bush E (1991) Hallucinogens and serotonergic mechanisms. Problems Drug Dependence 1991:131

    Google Scholar 

  • González-Maeso J, Sealfon SC (2012) Functional selectivity in GPCR heterocomplexes. Mini Rev Med Chem 12:851–855

    Article  PubMed  PubMed Central  Google Scholar 

  • Gonzalez-Maeso J, Sealfon SC (2009) Agonist-trafficking and hallucinogens. Curr Med Chem 16:1017–1027

    Article  CAS  PubMed  Google Scholar 

  • González-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q (2007) Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior. Neuron 53:439–452

    Article  PubMed  Google Scholar 

  • González-Maeso J, Yuen T, Ebersole BJ, Wurmbach E, Lira A, Zhou M, Weisstaub N, Hen R, Gingrich JA, Sealfon SC (2003) Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci 23:8836–8843

    Article  PubMed  PubMed Central  Google Scholar 

  • Gurschler I (2019) The fourfold discovery of Mescaline (1896–1919). Monatsh Chem-Chem Monthly 150:941–947

    Article  Google Scholar 

  • Halberstadt AL (2015) Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res 277:99–120

    Article  CAS  PubMed  Google Scholar 

  • Halberstadt AL, Chatha M, Chapman SJ, Brandt SD (2019) Comparison of the behavioral effects of mescaline analogs using the head twitch response in mice. J Psychopharmacol 33:406–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Halberstadt AL, Geyer MA (2010) LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT2A receptor. Psychopharmacology 208:179–189

    Article  CAS  PubMed  Google Scholar 

  • Halberstadt AL, Geyer MA (2013) Characterization of the head-twitch response induced by hallucinogens in mice. Psychopharmacology 227:727–739

    Article  CAS  PubMed  Google Scholar 

  • Halberstadt AL, Powell SB, Geyer MA (2013) Role of the 5-HT2A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice. Neuropharmacology 70:218–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hammond RS, Tull LE, Stackman RW (2004) On the delay-dependent involvement of the hippocampus in object recognition memory. Neurobiol Learn Mem 82:26–34

    Article  PubMed  Google Scholar 

  • Hatzidimitriou G, McCann UD, Ricaurte GA (1999) Altered serotonin innervation patterns in the forebrain of monkeys treated with (±) 3, 4-methylenedioxymethamphetamine seven years previously: factors influencing abnormal recovery. J Neurosci 19:5096–5107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hensler JG (2010) Serotonin in mood and emotion Handbook of behavioral neuroscience. Elsevier, pp 367–378

    Book  Google Scholar 

  • Herian M, Skawski M, Wojtas A, Sobocińska MK, Noworyta K, Gołembiowska K (2021) Tolerance to neurochemical and behavioral effects of the hallucinogen 25I-NBOMe. Psychopharmacology 238:2349–2364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hood SD, Hince DA, Robinson H, Cirillo M, Christmas D, Kaye JM (2006) Serotonin regulation of the human stress response. Psychoneuroendocrinology 31:1087–1097

    Article  CAS  PubMed  Google Scholar 

  • Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554

    Article  CAS  PubMed  Google Scholar 

  • Hur K-H, Kim S-E, Lee B-R, Ko Y-H, Seo J-Y, Kim S-K, Ma S-X, Kim Y-J, Jeong Y, Pham DT (2020) 25C-NBF, a new psychoactive substance, has addictive and neurotoxic potential in rodents. Arch Toxicol 94:2505–2516

    Article  CAS  PubMed  Google Scholar 

  • Jager G, De Win MM, Van Der Tweel I, Schilt T, Kahn RS, Van Den Brink W, Van Ree JM, Ramsey NF (2008) Assessment of cognitive brain function in ecstasy users and contributions of other drugs of abuse: results from an FMRI study. Neuropsychopharmacology 33:247–258

    Article  CAS  PubMed  Google Scholar 

  • Jaggar M, Vaidya VA (2018) 5-HT 2A receptors and BDNF regulation: implications for psychopathology 5-HT2A Receptors in the Central Nervous System. Springer, pp 395–438

    Google Scholar 

  • Jaster AM, Younkin J, Cuddy T, de la Fuente RM, Poklis JL, Dozmorov MG, González-Maeso J (2022) Differences across sexes on head-twitch behavior and 5-HT2A receptor signaling in C57BL/6J mice. Neurosci Lett 788:136836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelly CR, Sharif NA (2006) Pharmacological evidence for a functional serotonin-2B receptor in a human uterine smooth muscle cell line. J Pharmacol Exp Ther 317:1254–1261

    Article  CAS  PubMed  Google Scholar 

  • Kim M, Acharya S, Botanas CJ, Custodio RJ, Lee HJ, Sayson LV, Abiero A, Lee YS, Cheong JH, Kim K-m (2020) Catalpol and mannitol, two components of Rehmannia glutinosa, exhibit anticonvulsant effects probably via GABAA receptor regulation. Biomol Ther 28:137

    Article  CAS  Google Scholar 

  • Kim M, Custodio RJ, Botanas CJ, de la Peña JB, Sayson LV, Abiero A, Ryoo ZY, Cheong JH, Kim HJ (2019) The circadian gene, Per2, influences methamphetamine sensitization and reward through the dopaminergic system in the striatum of mice. Addict Biol 24:946–957

    Article  CAS  PubMed  Google Scholar 

  • Kraeuter A-K, Guest PC, Sarnyai Z (2019) The Y-maze for assessment of spatial working and reference memory in mice. Pre-clinical Model: Tech Protocol 1916:105–111

    Article  CAS  Google Scholar 

  • Kurrasch-Orbaugh DM, Parrish JC, Watts VJ, Nichols DE (2003) A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases. J Neurochem 86:980–991

    Article  CAS  PubMed  Google Scholar 

  • Lemaire D, Jacob P III, Shulgin A (1985) Ring-substituted β-methoxyphenethylamines: a new class of psychotomimetic agents active in man. J Pharm Pharmacol 37:575–577

    Article  CAS  PubMed  Google Scholar 

  • Leysen J (2004) 5-HT2 receptors. Curr Drug Targets-CNS Neurol Disord 3:11–26

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Zhong W, Wang D, Feng Q, Liu Z, Zhou J, Jia C, Hu F, Zeng J, Guo Q (2016) Serotonin neurons in the dorsal raphe nucleus encode reward signals. Nat Commun 7:1–15

    Google Scholar 

  • López-Giménez JF, González-Maeso J (2018) Hallucinogens and serotonin 5-HT 2A receptor-mediated signaling pathways. Curr Top Behav Neurosci 36:45–73

    Article  PubMed  PubMed Central  Google Scholar 

  • Maćkowiak M, Chocyk A, Fijał K, Czyrak A, Wędzony K (1999) c-Fos proteins, induced by the serotonin receptor agonist DOI, are not expressed in 5-HT2A positive cortical neurons. Mol Brain Res 71:358–363

    Article  PubMed  Google Scholar 

  • Mahmood I, Sahajwalla C (1999) Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug. Clin Pharmacokinet 36:277–287

    Article  CAS  PubMed  Google Scholar 

  • Malberg JE, Seiden LS (1998) Small changes in ambient temperature cause large changes in 3, 4-methylenedioxymethamphetamine (MDMA)-induced serotonin neurotoxicity and core body temperature in the rat. J Neurosci 18:5086–5094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin DA, Nichols CD (2018) The effects of hallucinogens on gene expression. Curr Top Behav Neurosci 36:137–158

    Article  CAS  PubMed  Google Scholar 

  • McCann UD, Szabo Z, Scheffel U, Dannals R, Ricaurte G (1998) Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings. Lancet 352:1433–1437

    Article  CAS  PubMed  Google Scholar 

  • Monte AP, Waldman SR, Marona-Lewicka D, Wainscott DB, Nelson DL, Sanders-Bush E, Nichols DE (1997) Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives. J Med Chem 40:2997–3008

    Article  CAS  PubMed  Google Scholar 

  • Newman-Tancredi A, Martel JC, Assié MB, Buritova J, Lauressergues E, Cosi C, Heusler P, Bruins Slot L, Colpaert F, Vacher B (2009) Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist. Br J Pharmacol 156:338–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181

    Article  CAS  PubMed  Google Scholar 

  • O’hearn E, Battaglia G, De Souza E, Kuhar M, Molliver M (1988) Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity. J Neurosci 8:2788–2803

    Article  PubMed  PubMed Central  Google Scholar 

  • Ortiz DM, Custodio RJP, Abiero A, Botanas CJ, Sayson LV, Kim M, Lee HJ, Kim HJ, Jeong Y, Yoon S (2021) The dopaminergic alterations induced by 4-F-PCP and 4-Keto-PCP may enhance their drug-induced rewarding and reinforcing effects: implications for abuse. Addict Biol 26:e12981

    Article  CAS  PubMed  Google Scholar 

  • Ortiz DMD, Kim M, Lee HJ, Botanas CJ, Custodio RJP, Sayson LV, Campomayor NB, Lee C, Lee YS, Cheong JH (2023) 4-F-PCP, a Novel PCP analog ameliorates the depressive-like behavior of chronic social defeat stress mice via NMDA receptor antagonism. Biomol Ther 31:227–239

    Article  CAS  Google Scholar 

  • Owen AM, Stern CE, Look RB, Tracey I, Rosen BR, Petrides M (1998) Functional organization of spatial and nonspatial working memory processing within the human lateral frontal cortex. Proc Natl Acad Sci 95:7721–7726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Páleníček T, Balíková M, Bubeníková-Valešová V, Horáček J (2008) Mescaline effects on rat behavior and its time profile in serum and brain tissue after a single subcutaneous dose. Psychopharmacology 196:51–62

    Article  PubMed  Google Scholar 

  • Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U (2020) The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. J Cereb Blood Flow Metab 40:1769–1777

    Article  PubMed  PubMed Central  Google Scholar 

  • Pokk P, Zharkovsky A (1998) The effects of buspirone on the behaviour of control and stressed mice. J Physiol Pharmacol 49:175–85

    CAS  PubMed  Google Scholar 

  • Pompeiano M, Palacios JM, Mengod G (1994) Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. Mol Brain Res 23:163–178

    Article  CAS  PubMed  Google Scholar 

  • Price AE, Sholler DJ, Stutz SJ, Anastasio NC, Cunningham KA (2019) Endogenous serotonin 5-HT2A and 5-HT2C receptors associate in the medial prefrontal cortex. ACS Chem Neurosci 10:3241–3248

    Article  CAS  PubMed  Google Scholar 

  • Prieto GA, Cotman CW (2017) Cytokines and cytokine networks target neurons to modulate long-term potentiation. Cytokine Growth Factor Rev 34:27–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qu Y, Villacreses N, Murphy DL, Rapoport SI (2005) 5-HT2A/2C receptor signaling via phospholipase A2 and arachidonic acid is attenuated in mice lacking the serotonin reuptake transporter. Psychopharmacology 180:12–20

    Article  CAS  PubMed  Google Scholar 

  • Reissig C, Eckler J, Rabin R, Winter J (2005) The 5-HT1A receptor and the stimulus effects of LSD in the rat. Psychopharmacology 182:197–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reneman L, Booij J, de Bruin K, Reitsma JB, de Wolff FA, Gunning WB, den Heeten GJ, van den Brink W (2001) Effects of dose, sex, and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons. Lancet 358:1864–1869

    Article  CAS  PubMed  Google Scholar 

  • Rickli A, Luethi D, Reinisch J, Buchy D, Hoener MC, Liechti ME (2015) Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2, 5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology 99:546–553

    Article  CAS  PubMed  Google Scholar 

  • Roth BL (2011) 5-HT2A serotonin receptor biology: interacting proteins, kinases and paradoxical regulation. Neuropharmacology 61:348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saraf TS, Felsing DE, Armstrong JL, Booth RG, Canal CE (2021) Evaluation of lorcaserin as an anticonvulsant in juvenile Fmr1 knockout mice. Epilepsy Res 175:106677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sayson LV, Botanas CJ, Custodio RJP, Abiero A, Kim M, Lee HJ, Kim HJ, Yoo SY, Lee KW, Ryu HW (2019) The novel methoxetamine analogs N-ethylnorketamine hydrochloride (NENK), 2-MeO-N-ethylketamine hydrochloride (2-MeO-NEK), and 4-MeO-N-ethylketamine hydrochloride (4-MeO-NEK) elicit rapid antidepressant effects via activation of AMPA and 5-HT2 receptors. Psychopharmacology 236:2201–2210

    Article  CAS  PubMed  Google Scholar 

  • Sayson LV, Custodio RJP, Ortiz DM, Lee HJ, Kim M, Jeong Y, Lee YS, Kim HJ, Cheong JH (2020) The potential rewarding and reinforcing effects of the substituted benzofurans 2-EAPB and 5-EAPB in rodents. Eur J Pharmacol 885:173527

    Article  CAS  PubMed  Google Scholar 

  • Schmidt CJ (1987) Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. J Pharmacol Exp Ther 240:1–7

    CAS  PubMed  Google Scholar 

  • Schmidt CJ, Levin JA, Lovenberg W (1987) In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoaminergic systems in the rat brain. Biochem Pharmacol 36:747–755

    Article  CAS  PubMed  Google Scholar 

  • Schmidt CJ, Wu L, Lovenberg W (1986) Methylenedioxymethamphetamine: a potentially neurotoxic amphetamine analogue. Eur J Pharmacol 124:175–178

    Article  CAS  PubMed  Google Scholar 

  • Serafine KM, Rice KC, France CP (2015) Directly observable behavioral effects of lorcaserin in rats. J Pharmacol Exp Ther 355:381–385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sewalia K, Watterson LR, Hryciw A, Belloc A, Ortiz JB, Olive MF (2018) Neurocognitive dysfunction following repeated binge-like self-administration of the synthetic cathinone 3, 4-methylenedioxypyrovalerone (MDPV). Neuropharmacology 134:36–45

    Article  CAS  PubMed  Google Scholar 

  • Shahar O, Botvinnik A, Esh-Zuntz N, Brownstien M, Wolf R, Lotan A, Wolf G, Lerer B, Lifschytz T (2022) Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 receptors in the head twitch response induced by 5-hydroxytryptophan and psilocybin: translational implications. Int J Mol Sci 23:14148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shulgin A, Shulgin A (1995) PIHKAL: a chemical love story. Transform Press

    Google Scholar 

  • Silvers JM, Harrod SB, Mactutus CF, Booze RM (2007) Automation of the novel object recognition task for use in adolescent rats. J Neurosci Methods 166:99–103

    Article  PubMed  PubMed Central  Google Scholar 

  • Steele TD, McCann UD, Ricaurte GA (1994) 3, 4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans. Addiction 89:539–551

    Article  CAS  PubMed  Google Scholar 

  • Stone DM, Johnson M, Hanson GR, Gibb JW (1988) Role of endogenous dopamine in the central serotonergic deficits induced by 3, 4-methylenedioxymethamphetamine. J Pharmacol Exp Ther 247:79–87

    CAS  PubMed  Google Scholar 

  • Tonello L, Cocchi M, Gabrielli F, Tuszynski JA (2015) On the possible quantum role of serotonin in consciousness. J Integr Neurosci 14:295–308

    Article  PubMed  Google Scholar 

  • Torres MA, Rezende C, Cassels BK (1998) α1-Adrenergic and 5-HT2-serotonergic effects of some β-alkoxy-β-phenylethylamines on isolated rat thoracic aorta. General Pharmacol: Vasc Syst 31:51–54

    Article  CAS  Google Scholar 

  • Tournois C, Mutel V, Manivet P, Launay J-M, Kellermann O (1998) Cross-talk between 5-hydroxytryptamine receptors in a serotonergic cell line: involvement of arachidonic acid metabolism. J Biol Chem 273:17498–17503

    Article  CAS  PubMed  Google Scholar 

  • Trachsel D (2012) Fluorine in psychedelic phenethylamines. Drug Test Anal 4:577–590

    Article  CAS  PubMed  Google Scholar 

  • Trulson ME, Crisp T, Henderson LJ (1983) Mescaline elicits behavioral effects in cats by an action at both serotonin and dopamine receptors. Eur J Pharmacol 96:151–154

    Article  CAS  PubMed  Google Scholar 

  • Tu Y-C, Huang D-Y, Shiah S-G, Wang J-S, Lin W-W (2013) Regulation of c-Fos gene expression by NF-κB: a p65 homodimer binding site in mouse embryonic fibroblasts but not human HEK293 cells. PLoS One 8:e84062

    Article  PubMed  PubMed Central  Google Scholar 

  • Vaidya VA, Marek GJ, Aghajanian GK, Duman RS (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci 17:2785–2795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van de Blaak FL, Dumont GJ (2022) Serotonin transporter availability, neurocognitive function and their correlation in abstinent 3, 4-methylenedioxymethamphetamine users. Hum Psychopharmacol Clin Exp 37:e2811

    Article  Google Scholar 

  • Villarreal A, Vidos C, MonteverdeBusso M, Cieri MB, Ramos AJ (2021) Pathological neuroinflammatory conversion of reactive astrocytes is induced by microglia and involves chromatin remodeling. Front Pharmacol 12:1448

    Article  Google Scholar 

  • Wold EA, Wild CT, Cunningham KA, Zhou J (2019) Targeting the 5-HT2C receptor in biological context and the current state of 5-HT2C receptor ligand development. Curr Top Med Chem 19:1381–1398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yadav PN, Kroeze WK, Farrell MS, Roth BL (2011) Antagonist functional selectivity: 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo. J Pharmacol Exp Ther 339:99–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The authors disclose receipt of the following financial support for the research, authorship, and/or publication of this article. This work was supported by the National Research Foundation (2020R1F1A1075633) and the Ministry of Food and Drug Safety (2214MFDS252 and 19182MFDS410) of South Korea.

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Authors and Affiliations

  1. Networking Group Aging, Department of Ergonomics, Leibniz Research Centre for Working Environment and Human Factors - IfADo, Ardeystrasse 67, Dortmund, 44139, Germany

    Raly James Perez Custodio

  2. Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795, Republic of Korea

    Darlene Mae Ortiz, Hyun Jun Lee, Leandro Val Sayson & Hee Jin Kim

  3. Department of Chemistry & Life Science, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795, Republic of Korea

    Mikyung Kim

  4. Medicinal Chemistry Laboratory, Department of Pharmacy & Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea

    Yong Sup Lee

  5. Department of Pharmacology, College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea

    Kyeong-Man Kim

  6. Institute for New Drug Development, College of Pharmacy, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju, Jeollabuk-do, 54896, Republic of Korea

    Jae Hoon Cheong

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  1. Raly James Perez Custodio
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Contributions

R.J.P.C.—study design and overall conceptualization, data acquisition and analysis, and preparation of original draft; H.J.K. and J.H.C.—funding acquisition and study supervision; Y.S.L.—drug synthesis and study supervision; K.-M.K.—binding and uptake studies; D.M.O, H.J.L., L.V.S., and M.K.—data acquisition and analysis and interpretation; All authors critically reviewed and edited the manuscript and approved its final version.

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Correspondence to Raly James Perez Custodio, Jae Hoon Cheong or Hee Jin Kim.

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Dr. Raly James Perez Custodio was a former member of Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarang-ro, Nowon-gu, Seoul, 01795, Republic of Korea and the Institute for New Drug Development, College of Pharmacy, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do 54896, Republic of Korea; Dr. Darlene Mae Ortiz is currently affiliated with the College of Pharmacy, Dongduk Women's University, 60 Hwarang-ro, Seongbuk-gu, Seoul, 02748, Republic of Korea.

This article belongs to a Special Issue on Psychedelics 2024.

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Custodio, R.J.P., Ortiz, D.M., Lee, H.J. et al. Serotonin 2C receptors are also important in head-twitch responses in male mice. Psychopharmacology (2023). https://doi.org/10.1007/s00213-023-06482-9

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