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.
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
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
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
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
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
Braff D, Geyer MA (1990) Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry 47:181–188
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
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
Cook JD, Ellinwood EH, Wilson WP (1968) Auditory habituation at primary cortex as a function of stimulus rate. Exp Neurobiol 21:167–175
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
Eccles JC (1969) The inhibitory pathways of the central nervous system. University Press, Liverpool
Franklin K, Paxinos G (1997) The Mouse brain in stereotaxic coordinates. Academic, San Diego, CA
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
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
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
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
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
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
Gray R, Rajan AS, Radcliffe KA et al (1996) Hippocampal synaptic transmission enhanced by low concentrations of nicotine. Nature 383:713–716
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
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
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
Leonard S (2003) Consequences of low levels of nicotinic acetylcholine receptors in schizophrenia for drug development. Drug Dev Res 60:127–136
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
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
Luntz-Leybman V, Bickford PC, Freedman R (1992) Cholinergic gating of response to auditory stimuli in rat hippocampus. Brain Res 587:130–136
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
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
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
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
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
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
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
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
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
O'Neill HC, Schmitt MP, Stevens KE (2003) Lithium alters measures of auditory gating in two strains of mice. Biol Psychiatry 54:847–853
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
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
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
Simosky JK, Stevens KE, Freedman R (2002) Nicotinic agonists and psychosis. Curr Drug Targets CNS Neurol Disord 1:149–162
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
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
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
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
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
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
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
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
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
Ward JM, Cockcroft GG, Lunt FSS, Wonnacott S (1990) Methyllycaconitine: a selective probe for neuronal α-bungarotoxin binding sites. FEBS Lett 270:45–48
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
Author information
Authors and Affiliations
Corresponding author
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-005-0142-0