RATIONALE: Insufficient inhibitory processing of the P50 auditory evoked potential (AEP) is observed in most schizophrenia patients and is not improved by typical antipsychotic drugs, such as haloperidol. This inhibitory processing deficit is associated with a subnormal level of hippocampal alpha7 nicotinic receptors (nAChRs), and drugs that activate these receptors normalize the deficit. The atypical antipsychotic clozapine also normalizes this deficit in schizophrenia patients, but by an unknown mechanism. OBJECTIVE: Similar to schizophrenia patients, DBA/2 mice spontaneously exhibit a deficit in inhibitory processing of the P20-N40 AEP, which is a rodent analogue of the human P50 AEP. The present study determined whether clozapine improved this deficit in DBA/2 mice, and by what mechanism. METHOD: Using a conditioning-testing paradigm with paired auditory stimuli to assess inhibitory P20-N40 AEP processing in DBA/2 mice, the effects of clozapine (0.1, 1, 3.33, or 10 mg/kg, i.p.) and haloperidol (1 mg/kg, i.p.) were assessed. The effect of clozapine (1 mg/kg) was assessed alone and after pre-administration of either alpha-bungarotoxin, an alpha7 nAChR antagonist, or dihydro-beta-erythroidine, an alpha4beta2 nAChR antagonist. RESULTS: In a dose-dependent manner, clozapine improved the deficient inhibitory processing of the P20-N40 AEP normally exhibited by DBA/2 mice. Like alpha7 agonists, 1 mg/kg clozapine selectively increased the inhibition of the P20-N40 response to the second of paired auditory stimuli. The normalizing effect of 1 mg/kg clozapine was blocked by alpha-bungarotoxin, but not by dihydro-beta-erythroidine. Haloperidol did not improve DBA/2's deficient P20-N40 AEP processing. CONCLUSIONS: Clozapine improved the deficient inhibitory processing of the P20-N40 AEP in DBA/2 mice, apparently through stimulation of alpha7 nicotinic receptors. This effect was not shared by the typical antipsychotic haloperidol.
RATIONALE: Insufficient inhibitory processing of the P50 auditory evoked potential (AEP) is observed in most schizophreniapatients and is not improved by typical antipsychotic drugs, such as haloperidol. This inhibitory processing deficit is associated with a subnormal level of hippocampal alpha7 nicotinic receptors (nAChRs), and drugs that activate these receptors normalize the deficit. The atypical antipsychotic clozapine also normalizes this deficit in schizophreniapatients, but by an unknown mechanism. OBJECTIVE: Similar to schizophreniapatients, DBA/2mice spontaneously exhibit a deficit in inhibitory processing of the P20-N40 AEP, which is a rodent analogue of the human P50 AEP. The present study determined whether clozapine improved this deficit in DBA/2mice, and by what mechanism. METHOD: Using a conditioning-testing paradigm with paired auditory stimuli to assess inhibitory P20-N40 AEP processing in DBA/2mice, the effects of clozapine (0.1, 1, 3.33, or 10 mg/kg, i.p.) and haloperidol (1 mg/kg, i.p.) were assessed. The effect of clozapine (1 mg/kg) was assessed alone and after pre-administration of either alpha-bungarotoxin, an alpha7 nAChR antagonist, or dihydro-beta-erythroidine, an alpha4beta2 nAChR antagonist. RESULTS: In a dose-dependent manner, clozapine improved the deficient inhibitory processing of the P20-N40 AEP normally exhibited by DBA/2mice. Like alpha7 agonists, 1 mg/kg clozapine selectively increased the inhibition of the P20-N40 response to the second of paired auditory stimuli. The normalizing effect of 1 mg/kg clozapine was blocked by alpha-bungarotoxin, but not by dihydro-beta-erythroidine. Haloperidol did not improve DBA/2's deficient P20-N40 AEP processing. CONCLUSIONS:Clozapine improved the deficient inhibitory processing of the P20-N40 AEP in DBA/2mice, apparently through stimulation of alpha7 nicotinic receptors. This effect was not shared by the typical antipsychotic haloperidol.
Authors: Robert Freedman; Ann Olincy; Randall G Ross; Merilyne C Waldo; Karen E Stevens; Lawrence E Adler; Sherry Leonard Journal: Curr Psychiatry Rep Date: 2003-06 Impact factor: 5.285
Authors: Karen E Stevens; Brandon Cornejo; Catherine E Adams; Lijun Zheng; Joan Yonchek; Keith L Hoffman; Uwe Christians; William R Kem Journal: Brain Res Date: 2010-07-03 Impact factor: 3.252
Authors: Philipp A Csomor; Katrin H Preller; Mark A Geyer; Erich Studerus; Theodor Huber; Franz X Vollenweider Journal: Neuropsychopharmacology Date: 2014-05-07 Impact factor: 7.853
Authors: Robert Freedman; Ann Olincy; Robert W Buchanan; Josette G Harris; James M Gold; Lynn Johnson; Diana Allensworth; Alejandrina Guzman-Bonilla; Bettye Clement; M Patricia Ball; Jay Kutnick; Vicki Pender; Laura F Martin; Karen E Stevens; Brandie D Wagner; Gary O Zerbe; Ferenc Soti; William R Kem Journal: Am J Psychiatry Date: 2008-04-01 Impact factor: 18.112