, Volume 193, Issue 1, pp 45–54

Putative antipsychotics with pronounced agonism at serotonin 5-HT1A and partial agonist activity at dopamine D2 receptors disrupt basal PPI of the startle reflex in rats

  • Agnès L. Auclair
  • Alexandra Galinier
  • Joël Besnard
  • Adrian Newman-Tancredi
  • Ronan Depoortère
Original Investigation



Prepulse inhibition (PPI) of the startle reflex has been extensively studied because it is disrupted in several psychiatric diseases, most notably schizophrenia. In rats, and to a lesser extent, in humans, PPI can be diminished by dopamine (DA) D2/D3 and serotonin 5-HT1A receptor agonists. A novel class of potential antipsychotics (SSR181507, bifeprunox, and SLV313) possess partial agonist/antagonist properties at D2 receptors and various levels of 5-HT1A activation.

Materials and methods

It thus appeared warranted to assess, in Sprague-Dawley rats, the effects of these antipsychotics on basal PPI.


SSR181507, sarizotan, and bifeprunox decreased PPI, with a near-complete abolition at 2.5–10 mg/kg; SLV313 had a significant effect at 0.16 mg/kg only. Co-treatment with the 5-HT1A receptor antagonist WAY100,635 (0.63 mg/kg) showed that the 5-HT1A agonist activity of SSR181507 was responsible for its effect. By contrast, antipsychotics with low affinity and/or efficacy at 5-HT1A receptors, such as aripiprazole (another DA D2/D3 and 5-HT1A ligand), and established typical and atypical antipsychotics (haloperidol, clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) had no effect on basal PPI (0.01–2.5 to 2.5–40 mg/kg).


The present data demonstrate that some putative antipsychotics with pronounced 5-HT1A agonist activity, coupled with partial agonist activity at DA D2 receptors, markedly diminish PPI of the startle reflex in rats.


These data raise the issue of the influence of such compounds on sensorimotor gating in humans.


5-HT1A agonist Antipsychotics Dopamine D2 antagonist Prepulse inhibition Sensorimotor gating Startle reflex 


  1. Abel KM, Allin MP, Hemsley DR, Geyer MA (2003) Low dose ketamine increases prepulse inhibition in healthy men. Neuropharmacology 44:729–737PubMedCrossRefGoogle Scholar
  2. Auclair AL, Kleven MS, Besnard J, Depoortere R, Newman-Tancredi A (2006) Actions of novel antipsychotic agents on apomorphine-induced PPI disruption: influence of combined serotonin 5-HT1A receptor activation and dopamine D2 receptor blockade. Neuropsychopharmacology 31:1900–1909PubMedCrossRefGoogle Scholar
  3. Bantick RA, Deakin JF, Grasby PM (2001) The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics? J Psychopharmacol 15:37–46PubMedGoogle Scholar
  4. Bartoszyk GD, Van Amsterdam C, Greiner HE, Rautenberg W, Russ H, Seyfried CA (2004) Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile. J Neural Transm 111:113–126PubMedCrossRefGoogle Scholar
  5. Bibbiani F, Oh JD, Chase TN (2001) Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models. Neurology 57:1829–1834PubMedGoogle Scholar
  6. Boulay D, Depoortere R, Louis C, Perrault G, Griebel G, Soubrie P (2004) SSR181507, a putative atypical antipsychotic with dopamine D2 antagonist and 5-HT1A agonist activities: improvement of social interaction deficits induced by phencyclidine in rats. Neuropharmacology 46:1121–1129PubMedCrossRefGoogle Scholar
  7. Braff D, Stone C, Callaway E, Geyer M, Glick I, Bali L (1978) Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology 15:339–343PubMedCrossRefGoogle Scholar
  8. Broekkamp CLE, Oosterloo SK, Berendsen HHG, van Delft AML (1988) Effects of metergoline, fenfluramine, and 8-OH-DPAT on catalepsy induced by haloperidol or morphine. Naunyn Schmiedebergs Arch Pharmacol 338:191–195PubMedCrossRefGoogle Scholar
  9. Bruins Slot LA, De Vries L, Newman-Tancredi A, Cussac D (2006) Differential profile of antipsychotics at serotonin 5-HT1A and dopamine D2S receptors coupled to extracellular signal-regulated kinase. Eur J Pharmacol 534:63–70PubMedCrossRefGoogle Scholar
  10. Claustre Y, Peretti DD, Brun P, Gueudet C, Allouard N, Alonso R et al (2003) SSR181507, a dopamine D2 receptor antagonist and 5-HT1A receptor agonist. I: neurochemical and electrophysiological profile. Neuropsychopharmacology 28:2064–2076PubMedGoogle Scholar
  11. Cosi C, Carilla-Durand E, Assié MB, Ormière AM, Maraval M, Leduc N et al (2006) Partial agonism of the antipsychotics SSR181507, aripiprazole and bifeprunox at D2 receptors: G-protein activation and prolactin release. Eur J Pharmacol 535:135–144PubMedCrossRefGoogle Scholar
  12. Depoortere R, Boulay D, Perrault G, Bergis O, Decobert M, Francon D et al (2003) SSR181507, a dopamine D2 receptor antagonist and 5-HT1A receptor agonist. II: behavioral profile predictive of an atypical antipsychotic activity. Neuropsychopharmacology 28:1889–1902PubMedGoogle Scholar
  13. Depoortere R, Auclair AL, Bardin L, Bruins Slot L, Kleven M, Newman-Tancredi A (2007) F15063, a compound with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: III) Profile in tests predictive of activity against cognitive deficits and negative symptoms of schizophrenia. Br J Pharmacol DOI 10.1038/sj.bjp.0707160
  14. Dulawa SC, Gross C, Stark KL, Hen R, Geyer MA (2000) Knockout mice reveal opposite roles for serotonin 1A and 1B receptors in prepulse inhibition. Neuropsychopharmacology 22:650–659PubMedCrossRefGoogle Scholar
  15. Feenstra RW, de Moes J, Hofma JJ, Kling H, Kuipers W, Long SK et al (2001) New 1-aryl-4-(biarylmethylene)piperazines as potential atypical antipsychotics sharing dopamine D2-receptor and serotonin 5-HT1A-receptor affinities. Bioorg Med Chem Lett 11:2345–2349PubMedCrossRefGoogle Scholar
  16. Feenstra RW, Long SK, Kuipers W, van der Heyden JA, Tulp MT, Kruse CG (2002) New approaches for psychosis treatment: design, synthesis and SAR of ligands binding to dopamine D2 and serotonin 5-HT1A receptors. Drugs of the future. XVIIth International Symposium on Medicinal Chemistry. 27(Suppl A):P237Google Scholar
  17. Freedman R, Olincy A, Ross RG, Waldo MC, Stevens KE, Adler LE et al (2003) The genetics of sensory gating deficits in schizophrenia. Curr Psychiatry Rep 5:155–161PubMedCrossRefGoogle Scholar
  18. Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology 156:117–154PubMedCrossRefGoogle Scholar
  19. Goff DC, Midha KK, Brotman AW, McCormick S, Waites M, Amico ET (1991) An open trial of buspirone added to neuroleptics in schizophrenic patients. J Clin Psychopharmacol 11:193–197PubMedGoogle Scholar
  20. Gogos A, Nathan PJ, Guille V, Croft RJ, van den Buuse M (2006) Estrogen prevents 5-HT1A receptor-induced disruptions of prepulse inhibition in healthy women. Neuropsychopharmacology 31:885–889PubMedCrossRefGoogle Scholar
  21. Gouzoulis-Mayfrank E, Heekeren K, Thelen B, Lindenblatt H, Kovar KA, Sass H, Geyer MA (1998) Effects of the hallucinogen psilocybin on habituation and prepulse inhibition of the startle reflex in humans. Behav Pharmacol 9:561–566PubMedCrossRefGoogle Scholar
  22. Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O’Laughlin IA, Meltzer HY (2001) 5-HT2A and D2 receptor blockade increases cortical DA release via 5-HT1A receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 76:1521–1531PubMedCrossRefGoogle Scholar
  23. Invernizzi RW, Cervo L, Samanin R (1988) 8-Hydroxy-2-(di-n-propylamino) tetralin, a selective serotonin1A receptor agonist, blocks haloperidol-induced catalepsy by an action on raphe nuclei medianus and dorsalis. Neuropharmacology 27:515–518PubMedCrossRefGoogle Scholar
  24. Kapur S, Remington G (1996) Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 153:466–476PubMedGoogle Scholar
  25. Kapur S, Remington G (2001) Dopamine D2 receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 50:873–883PubMedCrossRefGoogle Scholar
  26. Kleven M, Barret-Grévoz C, Bruins Slot L, Newman-Tancredi A (2005) Novel antipsychotic agents with 5-HT1A agonist properties: role of 5-HT1A receptor activation in attenuation of catalepsy induction in rats. Neuropharmacology 49:135–143PubMedCrossRefGoogle Scholar
  27. Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA et al (1999) Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 20:612–627PubMedCrossRefGoogle Scholar
  28. Leysen J (2000) Receptor profile of antipsychotics. In: Ellenbroek BA, Cools AR (eds) Atypical antipsychotics. Birkhauser, Basel, Switzerland, pp 57–81Google Scholar
  29. Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology 94:507–514PubMedCrossRefGoogle Scholar
  30. McCreary AC, Glennon J, Tuinstra T, Herremans AHJ, van der Heyden JA, Feenstra RW et al (2002) SLV313: a novel antipsychotic with additional antidepressant and anxiolytic-like actions. Eur Neuropsychopharmacol 12(Suppl 3):P.2.046Google Scholar
  31. Millan MJ (2000) Improving the treatment of schizophrenia: focus on serotonin 5-HT1A receptors. J Pharmacol Exp Ther 295:853–861PubMedGoogle Scholar
  32. Millan MJ, Brocco M, Veiga S, Cistarelli L, Melon C, Gobert A (1998) WAY 100,635 enhances both the ‘antidepressant’ actions of duloxetine and its influence on dialysate levels of serotonin in frontal cortex. Eur J Pharmacol 341:165–167PubMedCrossRefGoogle Scholar
  33. Moser PC, Hitchcock JM, Lister S, Moran PM (2000) The pharmacology of latent inhibition as an animal model of schizophrenia. Brain Res Rev 33:275–307PubMedCrossRefGoogle Scholar
  34. Moss LE, Neppe VM, Drevets WC (1993) Buspirone in the treatment of tardive dyskinesia. J Clin Psychopharmacol 13:204–209PubMedCrossRefGoogle Scholar
  35. Muller TJ, Kalus P, Strik WK (2001) The neurophysiological meaning of auditory P300 in subtypes of schizophrenia. World J Biol Psychiatry 2:9–17PubMedCrossRefGoogle Scholar
  36. Myers JL, Well AD (1995) Research design and statistical analysis. Lawrence Erlbaum Associates, Hillsdale, New JerseyGoogle Scholar
  37. Nanry KP, Tilson HA (1989) The role of 5HT1A receptors in the modulation of the acoustic startle reflex in rats. Psychopharmacology 97:507–513PubMedCrossRefGoogle Scholar
  38. Newman-Tancredi A, Assie MB, Leduc N, Ormiere AM, Danty N, Cosi C (2005) Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A receptors: affinity, efficacy and potential implications for treatment of schizophrenia. Int J Neuropsychopharmacol 8:341–356PubMedCrossRefGoogle Scholar
  39. Newman-Tancredi A, Assié M-B, Martel J-C, Cosi C, Heusler P, Bruins Slot L et al (2006) F15063, an innovative antipsychotic with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: I) in vitro, neurochemical and neuroendocrine profiles. Int J Neuropsychopharmacol 9(Supp 1):P01.164Google Scholar
  40. Newman-Tancredi A, Assié M-B, Martel J-C, Cosi C, Bruins Slot L, Palmier C, Rauly-Lestienne I, Cussac D (2007) F15063, a potential antipsychotic with D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties: I) in vitro receptor affinity and efficacy profile. Br J Pharmacol DOI 10.1038/sj.bjp.0707158
  41. Prinssen EP, Kleven MS, Koek W (1999) Interactions between neuroleptics and 5-HT1A ligands in preclinical behavioral models for antipsychotic and extrapyramidal effects. Psychopharmacology 144:20–29PubMedCrossRefGoogle Scholar
  42. Rabiner EA, Gunn RN, Wilkins MR, Sedman E, Grasby PM (2002) Evaluation of EMD 128 130 occupancy of the 5-HT1A and the D2 receptor: a human PET study with [11C]WAY-100635 and [11C]raclopride. J Psychopharmacol 16:195–199PubMedCrossRefGoogle Scholar
  43. Rigdon GC, Weatherspoon JK (1992) 5-Hydroxytryptamine 1A receptor agonists block prepulse inhibition of acoustic startle reflex. J Pharmacol Exp Ther 263:486–493PubMedGoogle Scholar
  44. Rollema H, Lu Y, Schmidt AW, Zorn SH (1997) Clozapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation. Eur J Pharmacol 338:R3–R5PubMedCrossRefGoogle Scholar
  45. Rollema H, Lu Y, Schmidt AW, Sprouse JS, Zorn SH (2000) 5-HT1A receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex. Biol Psychiatry 48:229–237PubMedCrossRefGoogle Scholar
  46. Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R (2003) Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 28:1400–1411PubMedCrossRefGoogle Scholar
  47. Sipes TA, Geyer MA (1995) 8-OH-DPAT disruption of prepulse inhibition in rats: reversal with (+)WAY 100,135 and localization of site of action. Psychopharmacology 117:41–48PubMedCrossRefGoogle Scholar
  48. Swerdlow NR, Braff DL, Geyer MA (2000) Animal models of deficient sensorimotor gating: what we know, what we think we know, and what we hope to know soon. Behav Pharmacol 11:185–204PubMedGoogle Scholar
  49. Swerdlow NR, Light GA, Cadenhead KS, Sprock J, Hsieh MH, Braff DL (2006) Startle gating deficits in a large cohort of patients with schizophrenia: relationship to medications, symptoms, neurocognition, and level of function. Arch Gen Psychiatry 63:1325–1335PubMedCrossRefGoogle Scholar
  50. Terranova J-P, Chabot C, Barnouin M-C, Perrault G, Depoortere R, Griebel G et al (2005) SSR181507, a dopamine D2 receptor antagonist and 5-HT1A receptor agonist, alleviates disturbances of novelty discrimination in rats, a model of selective attention deficit. Psychopharmacology 181:134–144PubMedCrossRefGoogle Scholar
  51. Varty GB, Higgins GA (1998) Dopamine agonist-induced hypothermia and disruption of prepulse inhibition: evidence for a role of D3 receptors? Behav Pharmacol 9:445–455PubMedCrossRefGoogle Scholar
  52. Vollenweider FX, Remensberger S, Hell D, Geyer MA (1999) Opposite effects of 3,4-methylenedioxymethamphetamine (MDMA) on sensorimotor gating in rats versus healthy humans. Psychopharmacology 143:365–372PubMedCrossRefGoogle Scholar
  53. Wadenberg ML, Cortizo L, Ahlenius S (1994) Evidence for specific interactions between 5-HT1A and dopamine D2 receptor mechanisms in the mediation of extrapyramidal motor functions in the rat. Pharmacol Biochem Behav 47:509–513PubMedCrossRefGoogle Scholar
  54. Weiner I (2003) The “two-headed” latent inhibition model of schizophrenia: modelling positive and negative symptoms and their treatment. Psychopharmacology 169:257–297PubMedCrossRefGoogle Scholar
  55. Weiner I, Shadach E, Tarrasch R, Kidron R, Feldon J (1996) The latent inhibition model of schizophrenia: further validation using the atypical neuroleptic, clozapine. Biol Psychiatry 40:834–843PubMedCrossRefGoogle Scholar
  56. Wolf W (2003) DU-127090 Solvay/H Lundbeck. Curr Opin Investig Drugs 4:72–76PubMedGoogle Scholar
  57. Yoshida K, Sugita T, Higuchi H, Hishikawa Y (1998) Effects of tandospirone on tardive dyskinesia and parkinsonian symptoms. Eur Psychiatry 13:421–422CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Agnès L. Auclair
    • 1
  • Alexandra Galinier
    • 1
  • Joël Besnard
    • 1
  • Adrian Newman-Tancredi
    • 1
  • Ronan Depoortère
    • 1
  1. 1.Division of Neurobiology 2Centre de Recherche Pierre FabreCastresFrance

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