Drugs that target serotonergic receptors

  • Alvin V. TerryJr.
Part of the Milestones in Drug Therapy MDT book series (MDT)


Of the neurotransmitter substances characterized to date, serotonin (5-hydroxytryptamine-5-HT) is perhaps one of the most extensively studied. Initial reports of its actions on smooth muscle appeared more than 50 years ago and it is now known to have widespread peripheral and central physiologic actions. In the periphery, the amine is released from platelets to activate clotting cascades and blood vessel constriction; in the gastrointestinal tract it inhibits gastric acid production and stimulates the contractions of smooth muscle [1]. In the central nervous system, 5HT is known to regulate or influence such diverse processes as activity patterns and circadian rhythm, food intake, sleep-wake cycles, aggressive behaviors, locomotion, thermoregulation, nociception, and sexual activity [2].


Morris Water Maze Passive Avoidance 5HT4 Receptor Agonist Serotonergic Receptor 5HT4 Agonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Fozard JR (ed.) (1989) The peripheral actions of 5-hydroxytryptamine. Oxford University Press, New YorkGoogle Scholar
  2. 2.
    Lucid I (1998) The spectrum of behaviors influenced by serotonin. Biol Psychiatry 44: 151–162CrossRefGoogle Scholar
  3. 3.
    Buhot MC, Martin S, Segu L (2000) Role of serotonin in memory impairment. Ann Med 32: 210–221PubMedCrossRefGoogle Scholar
  4. 4.
    Ellis KA, Nathan PJ (2001) The pharmacology of human working memory. Int J Neuropsychopharmacol 4: 299–313PubMedCrossRefGoogle Scholar
  5. 5.
    Altman HJ, Normile HJ (1988) What is the nature of the role of the serotonergic nervous system in learning and memory? Prospects for development of an effective treatment strategy for senile dementia. Neurobiol Aging 9: 627–638PubMedCrossRefGoogle Scholar
  6. 6.
    Briley M (1990) Biochemical strategies in the search for cognition enhancers. Pharmacopsychiatry 23(suppl): 75–80PubMedCrossRefGoogle Scholar
  7. 7.
    Flood JF, Cherkin A (1987) Fluoxetine enhances memory in mice. Psychopharmacology 93: 36–43PubMedCrossRefGoogle Scholar
  8. 8.
    Jaffard R, Mocaer E, Poignant JC, Micheau J, Marighetto A, Meunier M, Beracochea D (1991) Effects of tianeptine on spontaneous alternation, simple and concurrent spatial discrimination learning and on alcohol-induced alternation deficits in mice. Behav Pharmacol 2: 37–46PubMedCrossRefGoogle Scholar
  9. 9.
    Lipska BK, Jaskiw GE, Arya A, Weinberger DR (1992) Serotonin depletion causes long-term reduction of exploration in the rat. Pharmacol Biochem Behav 43: 1247–1252PubMedCrossRefGoogle Scholar
  10. 10.
    Wogar MA, Bradshaw C, Szabadi E (1992) Impaired acquisition of temporal differentiation performance following lesions of the ascending 5-hydroxytryptaminergic pathways. Psychopharmacology 111: 373–378CrossRefGoogle Scholar
  11. 11.
    Altman HJ, Normile HJ, Galloway MP, Ramirez A, Azmitia EC (1990) Enhanced spatial discrimination learning in rats following 5,7-DHT-induced serotonergic deafferentation of the hippocampus. Brain Res 518: 61–66PubMedCrossRefGoogle Scholar
  12. 12.
    Graham S, Ho M-Y, Bradshaw CM, Szabadi E (1994) Facilitated acquisition of a temporal discrimination following destruction of the ascending 5-hydroxytryptaminergic pathways. Psychopharmacology 116: 373–378PubMedCrossRefGoogle Scholar
  13. 13.
    Asin KE, Wirtshafter D, Fibiger HC (1985) Electrolytic, but not 5,7-dihydroxytryptamine, lesions of the nucleus medianus raphe impair acquisition of a radial L-maze task. Behav Neural Biol 44: 415–424PubMedCrossRefGoogle Scholar
  14. 14.
    Ricaurte GA, Markowska AL, Wenk GL, Hatzidimitriou G, Wlos J, Olton DS (1993) 3,4-Methylenedioxymethamphetamine, serotonin and memory. J Pharmacol Exp Ther 266: 1097PubMedGoogle Scholar
  15. 15.
    Meneses A (1999) 5HT system and cognition. Neurosci Biobehav Rev 23: 1111–1125PubMedCrossRefGoogle Scholar
  16. 16.
    Barnes NM, Sharp T (1999) A review of central 5HT receptors and their function. Neuropharmacology 38: 1083–1152PubMedCrossRefGoogle Scholar
  17. 17.
    Kia HK, Brisorgueil MJ, Daval G, Langlois X, Hamon M, Verge D (1996) SerotoninlA receptors are expressed by a subpopulation of cholinergic neurons in the rat medial septum and diagonal band of broca - a double immunocytochemical study. Neuroscience 75: 143–154CrossRefGoogle Scholar
  18. 18.
    Marcinkiewicz M, Verge D, Gozlan H, Pichat L, Hamon M (1984) Autoradiographic evidence for the heterogeneity of 5HT, sites in the rat brain. Brain Res 291: 159PubMedCrossRefGoogle Scholar
  19. 19.
    Middlemiss DN, Palmer AM, Edel N, Bowen DM (1986) Binding of the novel serotonin agonist 8-hydroxy-2-(di-n-propylamino)tetralin in normal and Alzheimer brain. J Neurochem 46: 993–996PubMedCrossRefGoogle Scholar
  20. 20.
    Cross AJ, Slater P, Perry E, Perry RH (1988) An autoradiographic analysis of serotonin receptors in human temporal cortex: Changes in Alzheimer-type dementia. Neurochem Int 13: 89–96PubMedCrossRefGoogle Scholar
  21. 21.
    Riad M, Emerit MB, Hamon M (1994) Neurotrophic effects of ipsapirone and other 5HT1A receptor agonists on septal cholinergic neurons in culture. Dev Brain Res 82: 245–258CrossRefGoogle Scholar
  22. 22.
    Bertrand F, Lehmann O, Galani R, Lazarus C, Jeltsch H, Cassel JC (2001) Effects of MDL 73005 on water-maze performances and locomotor activity in scopolamine-treated rats. Pharmacol Biochem Behav 68: 647–660CrossRefGoogle Scholar
  23. 23.
    Bass EW, Means LW, McMillen BA (1992) Buspirone impairs performance of a three-choice working memroy water escape task in rats. Brain Res Bull 28: 455PubMedCrossRefGoogle Scholar
  24. 24.
    Carli M, Samanin R (1992) 8-Hydroxy-2-(di-n-propylamino) tetralin impairs spatial learning in a water maze: role of post-synaptic 5HT1A receptors. Br J Pharmacol 105: 720PubMedCrossRefGoogle Scholar
  25. 25.
    Mendelson SD, Quartermain D, Francisco T, Shemer A (1993) 5HT 1A receptor agonists induce anterograde amnesia in mice through a postsynaptic mechanism. Eur J Pharmacol 236: 177–182PubMedCrossRefGoogle Scholar
  26. 26.
    Buhot MC, Naili S (1995) Changes in exploratory activity following stimulation of hippocampal 5HT1A and 5HT1B receptors in the rat. Hippocampus 5: 198–208PubMedCrossRefGoogle Scholar
  27. 27.
    Boschert U, Amara DA, Segu L, Hen R (1994) The mouse 5-hydroxytryptaminel B receptor is localized predominantly on axon terminals. Neuroscience 58: 167–182PubMedCrossRefGoogle Scholar
  28. 28.
    Maura G, Raiteri M (1986) Cholinergic terminals in rat hippocampus possess 5HTIB receptors mediating inhibition of acetylcholine release. Eur J Pharmacol 129: 333–337PubMedCrossRefGoogle Scholar
  29. 29.
    Ait Amara D, Segu L, Naili S, Buhot MC (1995) Serotonin 1B receptor regulation after dorsal subiculum deafferentation. Brain Res Bull 38: 17PubMedCrossRefGoogle Scholar
  30. 30.
    Buhot MC, Patra SK, Naili S (1995) Spatial memory deficits following stimulation of hippocampal 5HT1B receptors in the rat. Eur J Pharmacol 285: 221–228PubMedCrossRefGoogle Scholar
  31. 31.
    Meneses A, Tenon JA, Hong E (1997) Effects of the 5HT receptor antagonists GR127935 (5HTIB/1D) and MDL100907 (5HT2A) in the consolidation of learning. Behav Brain Res 89: 217–223PubMedCrossRefGoogle Scholar
  32. 32.
    Malleret G, Hen R, Guillou JL, Segu L, Buhot MC (1999) 5HT1B receptor knock-out mice exhibit increased exploratory activity and enhanced spatial memory performance in the Morris water maze. J Neurosci 19: 6157–6168PubMedGoogle Scholar
  33. 33.
    Winstanley CA, Chudasama Y, Dailey JW, Theobald DE, Glennon JC, Robbins TW (2003) Intraprefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats. Psychopharmacology (Berl) 167: 304–314Google Scholar
  34. 34.
    Altman HJ, Normile HJ (1987) Different temporal effects of serotonergic antagonists on passive avoidance retention. Pharmacol Biochem Behav 28: 353–359PubMedCrossRefGoogle Scholar
  35. 35.
    Strek KF, Spencer KR, DeNoble VJ (1989) Manipulation of serotonergic protects against a hypoxia-induced deficit of a passive avoidance response in rats. Phannacol Biochem Behav 33: 241–244CrossRefGoogle Scholar
  36. 36.
    DeNoble VJ, Schrack LM, Reigel AL, DeNoble KF (1991) Visual recognition memory in squirrel monkeys: Effects of serotonin antagonists on baseline and hypoxia-induced performance deficits. Pharmacol Biochem Behav 39: 991–996CrossRefGoogle Scholar
  37. 37.
    Williams GV, Rao SG, Goldman-Rakic PS (2002) The physiological role of 5HT2A receptors in working memory. J Neurosci 22: 2843–2854PubMedGoogle Scholar
  38. 38.
    Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 21 (2 Suppl): 106S–115SCrossRefGoogle Scholar
  39. 39.
    Kehne JH, Baron BM, Can AA, Chaney SF, Elands J, Feldman DJ, Frank RA, van Giersbergen PL, McCloskey TC, Johnson MP et al. (1996) Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a potent 5HT2A antagonist with a favorable CNS safety profile. J Pharmacol Exp Ther 277: 968–981PubMedGoogle Scholar
  40. 40.
    Offord SJ, Wong DE Nyberg S (1999) The role of positron emission tomography in the drug development of M100907, a putative antipsychotic with a novel mechanism of action. J Clin Pharmacol Suppl: 17S–24SGoogle Scholar
  41. 41.
    Kilpatrick GJ, Jones BI, Tyers MB (1987) Identification and distribution of 5HT3 receptors in rat brain using radioligand binding. Nature 330: 746–768PubMedCrossRefGoogle Scholar
  42. 42.
    Barnes JM, Barnes NM, Costall B, Naylor RJ, Tyers MB (1989) 5HT3 receptors mediate inhibition of acetylcholine release in cortical tissue. Nature 338[6218]: 762–763PubMedCrossRefGoogle Scholar
  43. 43.
    Waeber C, Hoyer D, Palacios JM (1989) 5-Hydroxytryptamine3 receptors in the human brain: Autoradiographic visualization using [3H]CS 205.030. Neuroscience 31: 393–400PubMedCrossRefGoogle Scholar
  44. 44.
    Maura G, Andrioli GC, Cavazzani P, Raiteri M (1992) 5-Hydroxytryptamine3 receptors sited on cholinergic axon terminals of human cerebral cortex mediate inhibition of acetylcholine release. J Neurochem 58[6]: 2334–2337PubMedCrossRefGoogle Scholar
  45. 45.
    Hong E, Meneses A (1996) Systemic injection of p-chloroamphetamine eliminates the effect of the 5HT3 compounds on learning. Pharmacol Biochem Behav 53: 765–769PubMedCrossRefGoogle Scholar
  46. 46.
    Carey GJ, Costall B, Domeney AM, Gerrard PA, Jones DN, Naylor RJ, Tyers MB (1992) Ondansetron and arecoline prevent scopolamine-induced cognitive deficits in the marmoset. Pharmacol Biochem Behav 42[1]: 75–83PubMedCrossRefGoogle Scholar
  47. 47.
    Fontana DJ, Daniels SE, Henderson C, Eglen RM, Wong EHF (1995) Ondansetron improves cognitive performance in the Morris water maze spatial navigation task. Psychopharmacology 120: 409–417PubMedCrossRefGoogle Scholar
  48. 48.
    Chugh Y, Saha N, Sankaranarayanan A, Datta H (1991) Enhancement of memory retrieval and attenuation of scopolamine-induced amnesia following administration of 5HT3 antagonist ICS 205–930. Phannacol Toxicol 69: 105–106CrossRefGoogle Scholar
  49. 49.
    Chugh Y, Saha N, Sankaranarayanan A, Sharma P (1991) Memory enhancing effects of granisetron (BRL 43694) in a passive avoidance task. Eur J Pharmacol 203: 121–123PubMedCrossRefGoogle Scholar
  50. 50.
    Pitsikas N, Brambilla A, Borsin F (1994) Effect of DAU 6215, a novel 5HT3 receptor antagonist, on scopolamine-induced amnesia in the rat in a spatial learning task. Pharmacol Biochem Behav 47: 95–99PubMedCrossRefGoogle Scholar
  51. 51.
    Terry Jr, AV, Buccafusco JJ, Prendergast MA, Jackson WJ, Fontana DL, Wong EHF, Whiting RL, Eglen RM (1996) The 5HT3 receptor antagonist, RS-56812, enhances delayed matching performance in monkeys. NeuroReport 8: 49–54PubMedCrossRefGoogle Scholar
  52. 52.
    Paxinos G (1985) The rat nervous system. Volume 1. Forebrain and midbrain. Academic Press, San DiegoGoogle Scholar
  53. 53.
    Eglen RM, Wong EHF, Dumuis A, Bockaert J (1995) Central 5HT4 receptors. Trends Pharmacol Sci 16: 391–398Google Scholar
  54. 54.
    Eglen RM (1997) 5-Hydroxytryptamine (5HT4) receptors and central nervous system function: An update. In: Jucker E (ed.): Progress in Drug Reseach 49: 9–21Google Scholar
  55. 55.
    Clark RD, Jahangir A, Langston JA, Weinhardt KK, Miller AB, Leung E, Eglen RM (1994) Ketones related to the benzoate 5HT4 receptor antagonist RS-23597 are high affinity partial agonists. Bio Org Med Chem Lett 4: 2477–2480CrossRefGoogle Scholar
  56. 56.
    Terry AV, Buccafusco JJ, Jackson WJ, Prendergast MA, Fontana DJ, Wong EH, Bonhaus DW, Weller P, Eglen RM (1998) Enhanced Delayed Matching Performance in Younger and Older Macaques administered the 5HT4 Receptor Agonist, RS-17017, Psychopharmacology 135: 407–415PubMedCrossRefGoogle Scholar
  57. 57.
    Moser PC, Bergis OE, Jegham S, Lochead A, Duconseille E, Terranova JP, Caille D, BerqueBestel I, Lezoualc’h F, Fischmeister R et al. (2002) SL65.0155, a novel 5-hydroxytryptamine(4) receptor partial agonist with potent cognition-enhancing properties. J Pharmacol Exp Ther 302: 731–741PubMedCrossRefGoogle Scholar
  58. 58.
    Dawson LA, Nguyen HQ, Li P (2001) The 5HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology 25: 662–668PubMedCrossRefGoogle Scholar
  59. 59.
    Woolley ML, Bentley JC, Sleight AJ, Marsden CA, Fone KC (2001) A role for 5HT6 receptors in retention of spatial learning in the Morris water maze. Neuropharmacology 41: 210–219PubMedCrossRefGoogle Scholar
  60. 60.
    Pouzet B, Didriksen M, Arnt J (2002) Effects of the 5HT(7) receptor antagonist SB-258741 in animal models for schizophrenia. Pharmacol Biochem Behav 71: 655–665PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2004

Authors and Affiliations

  • Alvin V. TerryJr.
    • 1
  1. 1.Program in Clinical and Experimental TherapeuticsUniversity of Georgia College of Pharmacy (Augusta Campus) and Small Animal Behavior Core, Medical College of GeorgiaAugustaUSA

Personalised recommendations