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5-HT modulation of auditory and visual sensorimotor gating: II. Effects of the 5-HT2A antagonist MDL 100,907 on disruption of sound and light prepulse inhibition produced by 5-HT agonists in Wistar rats

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Abstract

Increasing evidence suggests an important role of 5-HT, and 5-HT2A receptors in particular, in the etiology and treatment of schizophrenia. The prepulse inhibition paradigm is used as a model for sensorimotor gating processes that are disrupted in schizophrenia. The present study used the selective serotonin2A (5-HT2A) antagonist and putative antipsychotic agent MDL 100,907 to evaluate the contribution of 5-HT2A receptors to the disruptions of prepulse inhibition produced by several 5-HT agonists. The D2 antagonist haloperidol was used to evaluate a possible interaction with dopamine neurons. Sound or light prepulses were used to measure the generality of these drug effects on cross-modal prepulse inhibition. In the first study, MDL 100,907 antagonized the disruptions of auditory prepulse inhibition produced by the 5-HT releasing agents fenfluramine and 3,4-methyle-nedioxymethamphetamine (MDMA). These effects on prepulse inhibition were modality-specific in that MDL 100,907 did not reverse the effects of the 5-HT releasers on visual prepulse inhibition. Haloperidol did not alter the disruptive effects of MDMA or fenfluramine on either auditory or visual prepulse inhibition. In the second study, the direct acting 5-HT2A/2C receptor agonist/hallucinogen (+)1-4-iodo-2,5-dimethoxyphenyl-2-aminopropane (DOI) consistently disrupted auditory prepulse inhibition, and this effect was blocked by MDL 100,907 but not by haloperidol. A dose-response analysis demonstrated that MDL 100,907 potently antagonized DOI disrupted auditory prepulse inhibition, with an ED50 of 0.04 mg/kg, IP. DOI did not consistently disrupt visual prepulse inhibition. In summary, these data indicate that, at least under the conditions of the present studies, the disruptions of auditory prepulse inhibition produced by fenfluramine, MDMA, and DOI result from stimulation of 5-HT2A receptors. Furthermore, these disruptions do not involve direct or indirect stimulation of D2 receptors. The identity of the 5-HT receptor(s) underlying the disruptive effects of fenfluramine or MDMA on visual prepulse inhibition has not yet been identified. MDL 100,907 may be generally useful in CNS disorders in which excessive 5-HT2A receptor tone disrupts sensory gating processes.

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References

  • Appel NM, Mitchell WM, Garlick RK, Glennon RA, Teiteler M, DeSouza EB (1990) Autoradiographic characterization of (+)-1-(2,5-dimethoxy-4-[125I]iodophenyl)-2-aminopropane ([125I]DOI) binding to 5-HT2 and 5-HT1C receptors in rat brain. J Pharmacol Exp Ther 255:843–857

    Google Scholar 

  • Berger UV, Gu XF, Azmitia EC (1992) The substituted amphetamines 3,4-methyledioxymethamphetamine, methamphetamine,p-chloroamphetamine, and fenfluramine induce 5-hydroxy-tryptamine release via a common mechanism blocked by fluoxetine and cocaine. Eur J Pharmacol 215:153–160

    Google Scholar 

  • Braff DL, Geyer MA (1989) Sensorimotor gating and the neurobiology of schizophrenia: Human and animal model studies. In: Schultz S, Tamminga C (eds) Schizophrenia: scientific progress. Oxford University Press, NY, pp 124–136

    Google Scholar 

  • Breier A (1995) Serotonin, schizophrenia and antipsychotic drug action. Schizophr Res 14:187–202

    Google Scholar 

  • Geyer MA, Swerdlow NS, Mansbach RS, Braff DL (1990) Startle response models of sensorimotor gating and habituation deficits in schizophrenia. Brain Res Bull 25:485–498

    Google Scholar 

  • Glennon RA (1986) Discriminative stimulus properties of the serotonergic agent 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Life Sci 39:825–830

    Google Scholar 

  • Glennon RA, Titeler M, Young R (1986) Structure-activity relationships and mechanism of action of hallucinogenic agents based on drug discrimination and radioligand binding studies. Psychopharmacol Bull 22:953–958

    Google Scholar 

  • Grillon C, Ameli R, Charney DS, Krystal J, Braff DL (1992) Startle gating deficits occur across prepulse intensities in schizophrenic patients. Biol Psychiatry 32:939–943

    Google Scholar 

  • Hansson LO, Waters N, Winblad B, Gottfries CG, Carlsson A (1994) Evidence for biochemical heterogenity in schizophrenia: a multivariate study of monoaminergic indices in human post-mortal brain tissue. J Neural Trans — [Gen Sect] 98:217–235

    Google Scholar 

  • Hoffman HS, Ison JR (1980) Reflex modification in the domain of startle: I. Some empirical findings and their implications for how the nervous system processes sensory input. Psychol Rev 87:175–189

    Google Scholar 

  • Judd LL, McAdams L, Budnick B, Braff DL (1992) Sensory gating deficits in schizophrenia: new results. Am J Psychiatry 4:488–493

    Google Scholar 

  • Karper LP, Freeman GK, Morgan CA, Grillon C, Charney DS, Krystal JH (1993) Prepulse inhibition of the acoustic startle response and measures of attention in schizophrenic subjects. Schizophrenia Res 9:160

    Google Scholar 

  • Kehne JH, McCloskey TC, Taylor VL, Black CK, Fadayel GM, Schmidt CJ (1992) Effects of the serotonin releasers 3,4-methylenedioxymethamphetamine (MDMA), 4-chloroamphetamine (PCA) and fenfluramine on acoustic and tactile startle reflexes in rats. J Pharmacol Exp Ther 260:78–89

    Google Scholar 

  • Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Feldman DJ, Frank RA, van Giersbergen PLM, McCloskey TC, Johnson MP, McCarty DR, Poirot M, Senyah Y, Siegel BW, Widmaier C (1996a) Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a potent and selective 5-HT2A antagonist with a favorable CNS safety profile. J Pharmacol Exp Ther (in press)

  • Kehne JH, Padich RA, McCloskey TC, Taylor VL, Schmidt CJ (1996b) 5-HT modulation of auditory and visual sensorimotor gating: I. Effects of 5-HT releasers on sound and light prepulse inhibition in Wistar rats. Psychopharmacology 124:95–106

    Google Scholar 

  • Leysen JE, Janssen PMF, Schotte A, Luyten WHML, Megens AAHP (1993) Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors. Psychopharmacology 112:S40-S54

    Google Scholar 

  • Mansbach RS (1991) Effects of NMDA receptor ligands on sensorimotor gating in the rat. Eur J Pharmacol 202:61–66

    Google Scholar 

  • Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacology 94:507–514

    Google Scholar 

  • Mansbach RS, Braff DL, Geyer MA (1989) Prepulse inhibition of the acoustic startle response is disrupted by N-ethyl-3,4-methylenedioxymethamphetamine (MDEA) in the rat. Eur J Pharmacol 167:49–55.

    Google Scholar 

  • Marek GJ, Aghajanian GK (1994) Excitation of interneurons in piriform cortex by 5-hydroxytryptamine: blockade by MDL 100,907, a highly selective 5-HT2A receptor antagonist. Eur J Pharmacol 259:137–141

    Google Scholar 

  • Meltzer H (1991) Effects of antipsychotic drugs on serotonin receptors. Pharmacol Rev 43:587–604

    Google Scholar 

  • Meltzer H, Matzubara S, Lee J (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D1, D2 and serotonin2 pKi values. J Pharmacol Exp Ther 251:238–246

    Google Scholar 

  • Moser PC, Moran PM, Frank RA, Kehne JH (1996) Reversal of amphetamine-induced behaviours by MDL 100,907, a selective 5-HT2A antagonist. Behav Brain Res 13:163–167

    Google Scholar 

  • Palfreyman MG, Schmidt CJ, Sorensen SM, Dudley MW, Kehne JH, Moser P, Gittos MW, Carr AA (1993) Electrophysiological, biochemical, and behavioral evidence for 5-HT2 and 5-HT3 mediated control of dopaminergic function. In: Kahn Rs (ed) Proceedings of American College of Neuropsychology Symposium. Psychopharmacology 112:S60-S67

    Google Scholar 

  • Peroutka SJ (1994) Molecular biology of serotonin (5-HT) receptors. Synapse 18:241–260

    Google Scholar 

  • Pranzatelli MR (1990) Evidence for involvement of 5HT2 and 5-HT1C receptors in the behavioral effects of the 5-HT agonist 1-(2,5-dimethoxy-4-iodophenyl aminopropane)-2 (DOI). Neurosci Lett 115:74–80

    Google Scholar 

  • Rigdon GC, Viik K (1991) Prepulse inhibition as a screening test for potential antipsychotics. Drug Dev Res 23:91–99

    Google Scholar 

  • Rigdon GC, Weatherspoon JK (1992) 5-Hydroxytryptamine1A receptor agonists block prepulse inhibition of acoustic startle reflex. J Pharmacol Exp Ther 263:486–493

    Google Scholar 

  • Schmidt CJ, Kehne JH (1990) Neurotoxicity of MDMA: neurochemical effects. In: The neuropharmacology of serotonin. Ann NY Acad Sci 600:665–681

    Google Scholar 

  • Schmidt CJ, Taylor VL (1990) Reversal of the acute effects of 3,4-methylenedioxymethamphetamine by 5-HT uptake inhibitors. Eur J Pharmacol 181:133–136

    Google Scholar 

  • Schmidt CJ, Kehne JH, Carr AA, Fadayel GM, Humphreys TM, Ketteler HJ, McCloskey TC, Padich RA, Taylor VL, Sorensen SM (1993) Contribution of serotonin neurotoxins to understanding psychiatric disorders: the role of 5-HT2 receptors in schizophrenia and antipsychotic activity. Int Clin Psychopharmacol 8 [Suppl. 2] 25–32

    Google Scholar 

  • Schmidt CJ, Sorensen SM, Kehne JH, Carr AA, Palfreyman MG (1995) The role of 5-HT2A receptors in antipsychotic activity. Life Sci 56: 2209–2222

    Google Scholar 

  • Sipes TA, Geyer MA (1994) Multiple serotonin receptor subtypes modulate prepulse inhibition of the startle response in rats. Neuropharmacology 33: 441–448

    Google Scholar 

  • 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: 41–48

    Google Scholar 

  • Sorensen SM, Kehne JH, Fadayel GM, Humphreys TM, Ketteler HJ, Sullivan CK, Taylor VL, Schmidt CJ (1993) Characterization of the 5-HT2 receptor antagonist MDL 100,907 as a putative antipsychotic: Behavioral, electrophysiological and neurochemical studies. J Pharmacol Exp Ther 266: 684–691

    Google Scholar 

  • Swerdlow NR, Mansbach RS, Geyer MA, Pulvirenti L, Braff DL (1990) Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine. Psychopharmacology 100: 413–416

    Google Scholar 

  • Swerdlow NR, Keith VA, Braff DL, Geyer MA (1991) Effects of spiperone, SCH 23390, and clozapine on apomorphine inhibition of sensorimotor gating of the startle reflex in the rat. J Pharmacol Exp Ther 256: 530–536

    Google Scholar 

  • Swerdlow NR, Benbow CH, Zisook S, Geyer MA, Braff DL (1993) A preliminary assessment of sensorimotor gating in patients with obsessive compulsive disorder. Biol Psychiatry 33: 298–301

    Google Scholar 

  • Swerdlow NR, Paulsen J, Braff D.L, Butters N, Geyer MA, Swenson MR (1995) Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington's disease. J Neurol Neurosurg Psychiatry 58: 192–200

    Google Scholar 

  • Titeler M, Lyon RA, Davis KH, Glennon RA (1987) Selectivity of serotonergic drugs for multiple brain serotonin receptors. Biochem Pharmacol 36: 3265–3271

    Google Scholar 

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  1. Hoechst Marion Roussel Inc., 2110 E. Galbraith Road, 45215, Cincinnati, OH, USA

    R. A. Padich, T. C. McCloskey & J. H. Kehne

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  1. R. A. Padich
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  2. T. C. McCloskey
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  3. J. H. Kehne
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Padich, R.A., McCloskey, T.C. & Kehne, J.H. 5-HT modulation of auditory and visual sensorimotor gating: II. Effects of the 5-HT2A antagonist MDL 100,907 on disruption of sound and light prepulse inhibition produced by 5-HT agonists in Wistar rats. Psychopharmacology 124, 107–116 (1996). https://doi.org/10.1007/BF02245610

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  • DOI: https://doi.org/10.1007/BF02245610

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