5-HT2A/2B/2C Receptors, Memory and Therapeutic Targets

  • Alfredo Meneses
  • Rossana Nieto-Vera
  • Rosa María Anaya-Jiménez
Part of the The Receptors book series (REC, volume 32)


The 5-HT2 receptors subdivision into the 5-HT2A/2B/2C subtypes along with the advent of the selective antagonists has allowed a more detailed investigation on the role and therapeutic significance of these subtypes in cognitive functions. It is suggested that, 5-HT2B/2C receptors might be involved on memory formation probably mediating a suppressive or constraining action. Whether the drug-induced learning impairments in this study are explained by simple agonism, antagonism or inverse agonism at 5-HT2 receptors remains unclear at this time. Notably, the 5-HT2 receptor subtypes blockade may provide some benefit to reverse poor memory consolidation conditions associated with decreased cholinergic, glutamatergic, and/or serotonergic neurotransmission.


Autoshaping 5-HT2A/2B/2C Receptors Memory consolidation Serotonin Rats 



The author also wants to thank Sofia Meneses for the language review and the technical assistance of Roberto Gonzalez.


  1. 1.
    Barbas D, Zappulla JP, Angers S, Bouvier M, Castellucci VF, DesGroseillers L (2002) Functional characterization of a novel serotonin receptor (5-HTap2) expressed in the CNS of Aplysia Californica. J Neurochem 80:335–345CrossRefPubMedGoogle Scholar
  2. 2.
    Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152CrossRefPubMedGoogle Scholar
  3. 3.
    Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PPA (1994) International Union of Pharmacology classification of receptors for 5hydroxytryptamine (serotonin). Pharmacol Rev 46:157203Google Scholar
  4. 4.
    Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554CrossRefPubMedGoogle Scholar
  5. 5.
    Meneses A (1999) 5-HT system and cognition. Neurosci Biobehav Rev 23:1111–1125CrossRefPubMedGoogle Scholar
  6. 6.
    Meneses A (2013) 5-HT systems: emergent targets for memory formation and memory alterations. Rev Neurosci 24(6):629–664CrossRefPubMedGoogle Scholar
  7. 7.
    Harvey JA (1996) Serotonergic regulation of associative learning. Behav Brain Res 73:47–50CrossRefPubMedGoogle Scholar
  8. 8.
    Meneses A (2002) Involvement of 5-HT(2A/2B/2C) receptors on memory formation: simple agonism, antagonism, or inverse agonism? Cell Mol Neurobiol 22(5–6):675–688CrossRefPubMedGoogle Scholar
  9. 9.
    Meneses A (2014) Memory formation and memory alterations: 5-HT6 and 5-HT7 receptors, novel alternative. Rev Neurosci 25(3):325–356PubMedGoogle Scholar
  10. 10.
    De Ligt RAF, Kourounakis AP, Ijzerman AP (2000) Inverse agonism at G protein-coupled receptors: (patho)physiological relevance and implications for drug discovery. Br J Pharmacol 130:1–12CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Martin GR, Eglen RM, Hamblin MW, Hoyer D, Yocca F (1998) The structure and signaling properties of 5-HT receptors: an endless diversity. Trends Pharmacol Sci 19:2–4CrossRefPubMedGoogle Scholar
  12. 12.
    Canal CE, Morgan D, Felsing D, Kondabolu K, Rowland NE, Robertson KL, Sakhuja R, Booth RG (2014) A novel aminotetralin-type serotonin (5-HT) 2C receptor-specific agonist and 5-HT2A competitive antagonist/5-HT2B inverse agonist with preclinical efficacy for psychoses. J Pharmacol Exp Ther 349:310–318CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Williams GV, Rao SG, Goldman-Rakic PS (2002) The physiological role of 5-HT2A receptors in working memory. J Neurosci 22:2843–2854PubMedGoogle Scholar
  14. 14.
    Leone M, Attanasio A, Croci D, Filippini G, D’Amico D, Grazzi L, Nespolo A, Bussone G (2000) The serotonergic agentm- chlorophenylpiperazine induces migraine attacks: a controlled study. Neurology 55:169–139CrossRefGoogle Scholar
  15. 15.
    Orban G, Bombardi C, Marino Gammazza A, Colangeli R, Pierucci M, Pomara C, Pessia M, Bucchieri F, Arcangelo B, Smolders I, De Deurwaerdère P, Di Giovanni G (2014) Role(s) of the 5-HT2C receptor in the development of maximal dentate activation in the hippocampus of anesthetized rats. CNS Neurosci Ther 20:651–661CrossRefPubMedGoogle Scholar
  16. 16.
    Rauser L, Savage JE, Meltzer HY, Roth BL (2001) Inverse agonist actions of typical and typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine2C receptor. J Pharmacol Exp Ther 299:83–89PubMedGoogle Scholar
  17. 17.
    Vanover KE, Harvey SC, Son T, Bradley SR, Kold H, Makhay M, Veinbergs I, Spalding TA, Weiner DM, Andersson CM, Tolf BR, Brann MR, Hacksell U, Davis RE (2004) Pharmacological characterization of AC-90179 [2-(4-methoxyphenyl)-N-(4-methyl-benzyl)-N-(1-methyl-piperidin-4-yl)-acetamide hydrochloride]: a selective serotonin 2A receptor inverse agonist. J Pharmacol Exp Ther 310(3):943–951CrossRefPubMedGoogle Scholar
  18. 18.
    Meneses A, Perez-Garcia G, Liy-Salmeron G, Ponce-López T, Lacivita E, Leopoldo M (2015) 5-HT7 receptor activation by LP-211 increases LTM and cAMP production and attenuates memory impairment. Psychopharmacology 232(3):595–603CrossRefPubMedGoogle Scholar
  19. 19.
    Perez-Garcia G, Meneses A (2008) Memory formation, amnesia, improved memory and reversed amnesia: 5-HT role. Behav Brain Res 195(1):17–29CrossRefPubMedGoogle Scholar
  20. 20.
    Aloyo VJ, Berg KA, Spampinato U, Clarke WP, Harvey JA (2009) Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors. Pharmacol Ther 121(2):160–173CrossRefPubMedGoogle Scholar
  21. 21.
    Khilnani G, Khilnani AK (2011) Inverse agonism and its therapeutic significance. Indian J Pharmacol 43(5):492–501CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Navailles S, Lagière M, Le Moine C, De Deurwaerdère P (2013) Role of 5-HT2C receptors in the enhancement of c-Fos expression induced by a 5-HT2B/2C inverse agonist and 5-HT 2 agonists in the rat basal ganglia. Exp Brain Res 230(4):525–535CrossRefPubMedGoogle Scholar
  23. 23.
    Bombardi C, Di Giovanni G (2013) Functional anatomy of 5-HT2A receptors in the amygdala and hippocampal complex: relevance to memory functions. Exp Brain Res 230(4):427–439CrossRefPubMedGoogle Scholar
  24. 24.
    Zhang G, Ásgeirsdóttir HN, Cohen SJ, Munchow AH, Barrera MP, Stackman RW Jr (2013) Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice. Neuropharmacology 64:403–413CrossRefPubMedGoogle Scholar
  25. 25.
    Dougherty JP, Oristaglio J (2013) Chronic treatment with the serotonin 2A/2C receptor antagonist SR 46349B enhances the retention and efficiency of rule-guided behavior in mice. Neurobiol Learn Mem 103:50–63CrossRefPubMedGoogle Scholar
  26. 26.
    Boulougouris V, Robbins TW (2010) Enhancement of spatial reversal learning by 5-HT2C receptor antagonism is neuroanatomically specific. J Neurosci 30(3):930–938CrossRefPubMedGoogle Scholar
  27. 27.
    López-Vázquez MA, Gutiérrez-Guzmán BE, Cervantes M, Olvera-Cortés ME (2011) 5-HT2C receptors in learning. In: Di Giovanni G, et al. (eds) 5-HT 2C receptors in the pathophysiology of CNS disease. Springer Science + Business Media, New York: 461-507Google Scholar
  28. 28.
    Jensen AA, Plath N, Pedersen MH, Isberg V, Krall J, Wellendorph P, Stensbøl TB, Gloriam DE, Krogsgaard-Larsen P, Frølund B (2013) Design, synthesis, and pharmacological characterization of N- and O-substituted 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol analogues: novel 5-HT(2A)/5-HT(2C) receptor agonists with pro-cognitive properties. J Med Chem 56(3):1211–1227CrossRefPubMedGoogle Scholar
  29. 29.
    Puig MV, Gulledge AT (2011) Serotonin and prefrontal cortex function: neurons, networks, and circuits. Mol Neurobiol 44(3):449–464CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Hanks JB, González-Maeso J (2013) Animal models of serotonergic psychedelics. ACS Chem Neurosci 4(1):33–42CrossRefPubMedGoogle Scholar
  31. 31.
    Blasi G, De Virgilio C, Papazacharias A, Taurisano P, Gelao B, Fazio L, Ursini G, Sinibaldi L, Andriola I, Masellis R, Romano R, Rampino A, Di Giorgio A, Lo Bianco L, Caforio G, Piva F, Popolizio T, Bellantuono C, Todarello O, Kleinman JE, Gadaleta G, Weinberger DR, Bertolino A (2013) Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment. JAMA Psychiat 70(9):921–930CrossRefGoogle Scholar
  32. 32.
    Zhu B, Chen C, Loftus EF, Moyzis RK, Dong Q, Lin C (2013) True but not false memories are associated with the HTR2A gene. Neurobiol Learn Mem 106:204–209CrossRefPubMedGoogle Scholar
  33. 33.
    Ruan L, Lau BW, Wang J, Huang L, Zhuge Q, Wang B, Jin K, So KF (2014) Neurogenesis in neurological and psychiatric diseases and brain injury: from bench to bedside. Prog Neurobiol 115C:116–137CrossRefGoogle Scholar
  34. 34.
    Pennanen L, Van der Hart M, Yu L, Tecott LH (2013) Impact of serotonin (5-HT)2C receptors on executive control processes. Neuropsychopharmacology 38:957–967CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Heisler LK, Tecott LH (2009) Knockout Corner: neurobehavioural consequences of a serotonin 5-HT(2C) receptor gene mutation. Int J Neuropsychopharmacol 2(1):67–69CrossRefGoogle Scholar
  36. 36.
    Somerville EM, Horwood JM, Lee MD, Kennett GA, Clifton PG (2007) 5-HT(2C) receptor activation inhibits appetitive and consummatory components of feeding and increases brain c-fos immunoreactivity in mice. Eur J Neurosci 25:3115–3124CrossRefPubMedGoogle Scholar
  37. 37.
    Del'guidice T, Lemay F, Lemasson M, Levasseur-Moreau J, Manta S, Etievant A, Escoffier G, Doré FY, Roman FS, Beaulieu JM (2014) Stimulation of 5-HT2C receptors improves cognitive deficits induced by human tryptophan hydroxylase 2 loss of function mutation. Neuropsychopharmacology 39:1125–1134CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Nilsson SR, Somerville EM, Clifton PG (2013) Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task. PLoS One 30:e77762CrossRefGoogle Scholar
  39. 39.
    Cremer TI, Giorgetti M, Bosker FJ, Hogg S, Arnt J, Mork A, Honig G, Bogeso KP, Westerink BH, Den Boer H, Wikstrom HV, Tecott LH (2004) Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology 29:1782–1789CrossRefGoogle Scholar
  40. 40.
    Volkow ND, Baler RD, Goldstein RZ (2011) Addiction: pulling at the neural threads of social behaviors. Neuron 69:599–602CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Cunningham KA, Anastasio NC, Fox RG, Stutz SJ, Bubar MJ, Swinford SE, Watson CS, Gilbertson SR, Rice KC, Rosenzweig-Lipson S, Moeller FG (2013) Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction. ACS Chem Neurosci 4:110–121CrossRefPubMedGoogle Scholar
  42. 42.
    Fletcher PJ, Rizos Z, Noble K, Soko AD, Silenieks LB, Lê AD, Higgins GA (2012) Effects of the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist M100907 on nicotine self-administration and reinstatement. Neuropharmacology 62:2288–2298CrossRefPubMedGoogle Scholar
  43. 43.
    Oba A, Nakagawasai O, Onogi H, Nemoto W, Yaoita F, Arai Y, Tan-No K, Tadano T (2013) Chronic fluvoxamine treatment changes 5-HT(2A/2C) receptor-mediated behavior in olfactory bulbectomized mice. Life Sci 92:119–124CrossRefPubMedGoogle Scholar
  44. 44.
    Furr A, Lapiz-Bluhm MD, Morilak DA (2012) 5-HT2A receptors in the orbitofrontal cortex facilitate reversal learning and contribute to the beneficial cognitive effects of chronic citalopram treatment in rats. Int J Neuropsychopharmacol 15:1295–1305CrossRefPubMedGoogle Scholar
  45. 45.
    Meneses A (2002) Involvement of 5-HT2A/2B/2C receptors on memory formation: simple agonism, antagonism, or inverse agonism? Cell Mol Neurobiol 22:675–688CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Alfredo Meneses
    • 1
  • Rossana Nieto-Vera
    • 2
  • Rosa María Anaya-Jiménez
    • 2
  1. 1.Department of Pharmacobiology, CINVESTAVMéxico CityMexico
  2. 2.Facultad de Ciencias de la SaludUniversidad Anáhuac México NorteMéxico CityMexico

Personalised recommendations