Skip to main content
Log in

Tropisetron improves deficient inhibitory auditory processing in DBA/2 mice: role of α7 nicotinic acetylcholine receptors

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Deficient inhibitory processing of the P50 auditory evoked potential is a pathophysiological feature of schizophrenia. Several lines of evidence suggest that α7 nicotinic receptors play a critical role in this phenomenon. Similar to schizophrenic patients, DBA/2 mice spontaneously exhibit a deficit in inhibitory processing of the P20–N40 auditory evoked potential, which is thought to be a rodent analog of the human P50 auditory evoked potential.

Objective

The present study was undertaken to examine whether tropisetron, a partial agonist at α7 nicotinic receptors and an antagonist at 5-hydroxytryptamine-3 receptors, improves this deficit in DBA/2 mice.

Results

Administration of tropisetron (1 mg/kg i.p.) significantly improved the deficient inhibitory processing of the P20–N40 auditory evoked potential in DBA/2 mice. Coadministration of methyllycaconitine (MLA; 3 mg/kg i.p.), a partially selective antagonist at α7 nicotinic receptors, significantly blocked the normalizing effect of tropisetron. Furthermore, MLA alone did not alter the deficient inhibitory processing of the P20–N40 auditory evoked potential in DBA/2 mice.

Conclusions

The data suggest that tropisetron improves the deficient inhibitory processing of the P20–N40 auditory evoked potential in DBA/2 mice by effects on α7 and perhaps α4β2 nicotinic receptors. Tropisetron may be useful for the treatment of deficient inhibitory processing in schizophrenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Adler LE, Rose G, Freedman R (1986) Neurophysiological studies of sensory gating in rats: effects of amphetamine, phencyclidine and haloperidol. Biol Psychiatry 21:787–798

    Article  PubMed  CAS  Google Scholar 

  • Adler LE, Pang K, Gerhardt G, Rose GM (1988) Modulation of the gating of auditory evoked potentials by norepinephrine: pharmacological evidence obtained using a selective neurotoxin. Biol Psychiatry 24:179–190

    Article  PubMed  CAS  Google Scholar 

  • Adler LE, Olincy A, Waldo M, Harris JG, Griffith J, Stevens K, Flach K, Nagamoto H, Bickford P, Leonard S, Freedman R (1998) Schizophrenia, sensory gating, and nicotinic receptors. Schizophr Bull 24:189–202

    PubMed  CAS  Google Scholar 

  • Adler LE, Cawthra E, Donovan KA, Harris JG, Nagamoto H, Olincy A, Waldo M (2005) Ondansetron improves P50 auditory gating in medicated schizophrenic patients. Am J Psychiatry 162:386–388

    Article  PubMed  Google Scholar 

  • Braff D, Freedman R (2003) Endophenotypes in studies of the genetics of schizophrenia. In: Davis KL, Charney D, Coyle JT, Nemeroff CN (eds) Neuropsychopharmacology. The fifth generation of progress. Lippincott Williams & Wilkins, Philadelphia, PA, pp 703–716

    Google Scholar 

  • Braff D, Geyer MA (1990) Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry 47:181–188

    PubMed  CAS  Google Scholar 

  • Clarke PB, Rueben M (1996) Release of [3H]-noradrenaline from rat hippocampal synaptosomes by nicotine: mediation by different nicotinic receptor subtypes from striatal [3H]-dopamine release. Br J Pharmacol 117:595–606

    PubMed  CAS  Google Scholar 

  • Connolly PM, Maxwell CR, Kanes SJ, Abel T, Liang Y, Tokarczyk J, Bilker WB, Turetsky BI, Gur RE, Siegel SJ (2003) Inhibition of auditory evoked potentials and prepulse inhibition of startle in DBA/2J and DBA/2Hsd inbred mouse strains. Brain Res 992:85–95

    Article  PubMed  CAS  Google Scholar 

  • Cook JD, Ellinwood EH, Wilson WP (1968) Auditory habituation at primary cortex as a function of stimulus rate. Exp Neurobiol 21:167–175

    Article  CAS  Google Scholar 

  • Cullum CM, Harris JG, Waldo MC, Smernoff E, Madison A, Nagamoto HT, Griffith J, Adler LE, Freedman R (1993) Neurophysiological and neuropsychological evidence for attentional dysfunction in schizophrenia. Schizophr Res 10:131–141

    Article  PubMed  CAS  Google Scholar 

  • Eccles JC (1969) The inhibitory pathways of the central nervous system. University Press, Liverpool

    Google Scholar 

  • Franklin K, Paxinos G (1997) The Mouse brain in stereotaxic coordinates. Academic, San Diego, CA

    Google Scholar 

  • Frazier CJ, Rollins YD, Breese CR, Leonard S, Freedman R, Dunwiddie TV (1998) Acetylcholine activates an alpha-bungarotoxin-sensitive nicotinic current in rat hippocampal interneurons, but not pyramidal cells. J Neurosci 18:1187–1195

    PubMed  CAS  Google Scholar 

  • Freedman R, Adler LE, Gerhardt GA, Waldo M, Baker N, Rose GM, Drebing C, Nagamoto H, Bickford-Wimer P, Franks R (1987) Neurobiological studies of sensory gating in schizophrenia. Schizophr Bull 13:669–678

    PubMed  CAS  Google Scholar 

  • Freedman R, Adler LE, Bickford P, Byerley W, Coon H, Cullum CM, Griffith JM, Harris JG, Leonard S, Miller C, Myles-Worsey M, Nagamoto HT, Rose G, Waldo M (1994) Schizophrenia and nicotinic receptors. Harv Rev Psychiatry 2:179–192

    Article  PubMed  CAS  Google Scholar 

  • Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, Polymeropoulos M, Holik J, Hopkins J, Hoff M, Rosenthal J, Waldo MC, Reimherr F, Wender P, Yaw J, Young DA, Breese CR, Adams C, Patterson D, Adler LE, Kruglyak L, Leonard S, Byerley W (1997) Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci U S A 94:587–592

    Article  PubMed  CAS  Google Scholar 

  • Freedman R, Adams CE, Leonard S (2000) The alpha7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia. J Chem Neuroanat 20:299–306

    Article  PubMed  CAS  Google Scholar 

  • Grady SR, Grun EU, Marks MJ, Collins AC (1997) Pharmacological comparison of transient and persistent [3H]dopamine release from synaptosomes prepared from mouse striatum. J Pharmacol Exp Ther 282:32–43

    PubMed  CAS  Google Scholar 

  • Gray R, Rajan AS, Radcliffe KA et al (1996) Hippocampal synaptic transmission enhanced by low concentrations of nicotine. Nature 383:713–716

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto K, Koike K, Shimizu E, Iyo M (2005) α7 nicotinic receptor agonists as potential therapeutic drugs for schizophrenia. Curr Med Chem–CNS Agents 5:171–184

    CAS  Google Scholar 

  • Karadsheh MS, Shah MS, Tang X, Macdonald RL, Stitzel JA (2004) Functional characterization of mouse α4β2 nicotinic acetylcholine receptors stably expressed in HEK293T cells. J Neurochem 91:1138–1150

    Article  PubMed  CAS  Google Scholar 

  • Koike K, Hashimoto K, Takai N, Shimizu E, Komatsu N, Watanabe H, Nakazato M, Okamura N, Stevens KE, Freedman R, Iyo M (2005) Tropisetron improves deficits in auditory P50 suppression in schizophrenia. Schizophr Res 76:67–72

    Article  PubMed  Google Scholar 

  • Leonard S (2003) Consequences of low levels of nicotinic acetylcholine receptors in schizophrenia for drug development. Drug Dev Res 60:127–136

    Article  CAS  Google Scholar 

  • Leonard S, Adams C, Breese CR, Adler LE, Bickford P, Byerley W, Coon H, Griffith JM, Miller C, Myles-Worsley M, Nagamoto HT, Rollins Y, Stevens KE, Waldo M, Freedman R (1996) Nicotinic receptor function in schizophrenia. Schizophr Bull 22:431–445

    PubMed  CAS  Google Scholar 

  • Leonard S, Gault J, Hopkins J, Logel J, Vianzon R, Short M, Drebing C, Berger R, Venn D, Sirota P, Zerbe G, Olincy A, Ross RG, Adler LE, Freedman R (2002) Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry 59:1085–1096

    Article  PubMed  CAS  Google Scholar 

  • Luntz-Leybman V, Bickford PC, Freedman R (1992) Cholinergic gating of response to auditory stimuli in rat hippocampus. Brain Res 587:130–136

    Article  PubMed  CAS  Google Scholar 

  • Macor JE, Gurley D, Lanthorn T, Loch J, Mack RA, Mullen G, Tran O, Wright N, Gordon JC (2001) The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist. Bioorg Med Chem Lett 11:319–321

    Article  PubMed  CAS  Google Scholar 

  • Maricq AV, Peterson AS, Brake AJ, Myers RM, Julius D (1991) Primary structure and functional expression of the 5-HT3 receptor, a serotonin-gated ion channel. Science 254:432–437

    Article  PubMed  CAS  Google Scholar 

  • Martin LF, Kem WR, Freedman R (2004) Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia. Psychopharmacology (Berl) 174:54–64

    Article  CAS  Google Scholar 

  • Maxwell CR, Liang Y, Weightman BS, Kanes SJ, Abel T, Gur RE, Turetsky BI, Bilker WB, Lenox RH, Siegel SJ (2004) Effects of chronic olanzapine and haloperidol differ on the mouse N1 auditory evoked potential. Neuropsychopharmacology 29:739–746

    Article  PubMed  CAS  Google Scholar 

  • Miller C, Bickford PC, Luntz-Leybman V, Adler LE, Gerhardt GA, Freedman R (1992) Phenylcyclidine and auditory sensory gating in the hippocampus of the rat. Neuropharmacology 31:1041–1048

    Article  PubMed  CAS  Google Scholar 

  • Miner H, Bratcher NA, Bitner RS, Decker MW, Radek RJ (2004) Contribution of α4β2 receptor stimulation to the effects of nicotine on sensory gating in DBA/2 mice. Soc Neuro Abstract Viewer, Program no. 48.19

  • Miyazato H, Skinner RD, Garcia-Rill E (1999) Neurochemical modulation of the P13 midlatency evoked potential in the rat. Neuroscience 92:911–920

    Article  PubMed  CAS  Google Scholar 

  • Miyazato H, Skinner RD, Crews T, Williams K, Garcia-Rill E (2000) Serotonergic modulation of the P13 midlatency auditory evoked potential in the rat. Brain Res Bull 51:387–391

    Article  PubMed  CAS  Google Scholar 

  • Nagamoto HT, Adler LE, Hea RA, Griffith JM, McRae KA, Freedman R (1996) Gating of auditory P50 in schizophrenics: unique effects of clozapine. Biol Psychiatry 40:181–188

    Article  PubMed  CAS  Google Scholar 

  • Nagamoto HT, Adler LE, McRae KA, Huettl P, Cawthra E, Gerhardt G, Hea R, Griffith J (1999) Auditory P50 in schizophrenics on clozapine: improved gating parallels clinical improvement and changes in plasma 3-methoxy-4-hydroxyphenylglycol. Neuropsychobiology 39:10–17

    Article  PubMed  CAS  Google Scholar 

  • O'Neill HC, Schmitt MP, Stevens KE (2003) Lithium alters measures of auditory gating in two strains of mice. Biol Psychiatry 54:847–853

    Article  PubMed  CAS  Google Scholar 

  • Papke RL, Porter Papke JK, Rose GM (2004) Activity of alpha7-selective agonists at nicotinic and serotonin 5-HT3 receptors expressed in Xenopus oocytes. Bioorg Med Chem Lett 14:1849–1853

    Article  PubMed  CAS  Google Scholar 

  • Ramirez MJ, Cenarruzabeitia E, Lasheras B, Del Rio J (1996) Involvement of GABA systems in acetylcholine release induced by 5-HT3 receptor blockade in slices from rat entorhinal cortex. Brain Res 712:274–280

    Article  PubMed  CAS  Google Scholar 

  • Simosky JK, Stevens KE, Kem WR, Freedman R (2001) Intragastric DMXB-A, an alpha7 nicotinic agonist, improves deficient sensory inhibition in DBA/2 mice. Biol Psychiatry 50:493–500

    Article  PubMed  CAS  Google Scholar 

  • Simosky JK, Stevens KE, Freedman R (2002) Nicotinic agonists and psychosis. Curr Drug Targets CNS Neurol Disord 1:149–162

    Article  PubMed  CAS  Google Scholar 

  • Simosky JK, Stevens KE, Adler LE, Freedman R (2003) Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism. Psychopharmacology (Berl) 165:386–396

    CAS  Google Scholar 

  • Simosky JK, Stevens KE, Adler LE, Freedman R (2004) Atypical antipsychotics and auditory gating deficits: exploring the mechanism of normalization. Biol Psychiatry 55:8S–161S

    Google Scholar 

  • Simpson K, Spencer CM, McClellan KJ (2000) Tropisetron: an update of its use in the prevention of chemotherapy-induced nausea and vomiting. Drugs 59:1297–1315

    Article  PubMed  CAS  Google Scholar 

  • Stevens K, Wear K (1997) Normalizing effects of nicotine and a novel nicotinic agonist on hippocampal auditory gating in two animal models. Pharmacol Biochem Behav 57:869–874

    Article  PubMed  CAS  Google Scholar 

  • Stevens K, Freedman R, Collins A, Hall M, Leonard S, Marks MJ, Rose GM (1996) Genetic correlation of inhibitory gating of hippocampal auditory response and α-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains. Neuropsychopharmacology 15:152–162

    Article  PubMed  CAS  Google Scholar 

  • Stevens K, Kem W, Mahnir V, Freedman R (1998) Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice. Psychopharmacology (Berl) 136:320–327

    Article  CAS  Google Scholar 

  • Stevens K, Kem W, Freedman R (1999) Selective alpha-7 nicotinic receptor stimulation normalizes chronic cocaine-induced loss of hippocampal sensory inhibition in C3H mice. Biol Psychiatry 46:1443–1450

    Article  PubMed  CAS  Google Scholar 

  • Teneud L, Miyazato H, Skinner RD, Garcia-Rill E (2000) Cholinergic modulation of the sleep state-dependent P13 midlatency auditory evoked potential in the rat. Brain Res 884:196–200

    Article  PubMed  CAS  Google Scholar 

  • Turek JW, Kang CH, Campbell JE, Arneric SP, Sullivan JP (1995) A sensitive technique for the detection of the alpha 7 neuronal nicotinic acetylcholine receptor antagonist, methyllycaconitine, in rat plasma and brain. J Neurosci Methods 61:113–118

    Article  PubMed  CAS  Google Scholar 

  • Ward JM, Cockcroft GG, Lunt FSS, Wonnacott S (1990) Methyllycaconitine: a selective probe for neuronal α-bungarotoxin binding sites. FEBS Lett 270:45–48

    Article  PubMed  CAS  Google Scholar 

  • Willot J, Demuth R, Lu S, Van Bergem P (1982) Abnormal tonotopic organization in the ventral cochlear nucleus of the hearing-impaired DBA/2 mouse. Neurosci Lett 34:13–17

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kenji Hashimoto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hashimoto, K., Iyo, M., Freedman, R. et al. Tropisetron improves deficient inhibitory auditory processing in DBA/2 mice: role of α7 nicotinic acetylcholine receptors. Psychopharmacology 183, 13–19 (2005). https://doi.org/10.1007/s00213-005-0142-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-005-0142-0

Keywords

Navigation