Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism.
BACKGROUND
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.


METHODS
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.
Simosky
Johanna K
JK
Department of Pharmacology, University of Colorado Health Sciences Center, Campus Box C268-71, 4200 East 9th Avenue, Denver, CO 80262, USA. johanna.simosky@uchsc.edu
Stevens
Karen E
KE
Adler
Lawrence E
LE
Freedman
Robert
R
D000161:Acoustic Stimulation; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001308:Auditory Perceptual Disorders / Q000188:drug therapy*; D002038:Bungarotoxins / Q000494:pharmacology; D003024:Clozapine / Q000627:therapeutic use*; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004569:Electroencephalography; D005072:Evoked Potentials, Auditory / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology / Q000601:surgery; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor
D014150:Antipsychotic Agents; D002038:Bungarotoxins; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D004079:Dihydro-beta-Erythroidine; D003024:Clozapine; D006220:Haloperidol