Effects of acute and chronic clozapine on D-amphetamine-induced disruption of auditory gating in the rat.
BACKGROUND
Auditory gating deficits observed in patients with schizophrenia have been modeled in animals administered the indirect-acting monoaminergic agonist, D-amphetamine (AMPH). The atypical antipsychotic drug clozapine (CLOZ) reverses the disruption of auditory gating in schizophrenic patients. However, its effects on psychostimulant-induced deficits in animals have yet to be assessed.


OBJECTIVE
In the present series of experiments, an auditory evoked potential paradigm was used to: (a) confirm the ability of AMPH to alter auditory gating in the anesthetized rat, (b) specify the nature of the accompanying change(s) in evoked potential waveforms and (c) determine the effects of CLOZ administration on AMPH-induced alterations in auditory gating.


METHODS
We compared the effects of acute (5 mg/kg, i.p.) and chronic (28 days, 0.5 mg/ml in drinking water) CLOZ on AMPH-induced (1.8 mg/kg, i.p.) alterations in evoked potentials recorded in the hippocampus of anesthetized rats during presentation of a pair of identical tones. Gating was assessed by comparing the amplitude of conditioning and test responses in CLOZ and AMPH-treated rats.


RESULTS
The ratio of test to conditioning response amplitude (T/C ratio) was not altered by vehicle or CLOZ alone. However, T/C ratio was significantly increased following AMPH due to suppression of the conditioning response. Acute but not chronic CLOZ attenuated but did not prevent the increase in T/C ratio.


CONCLUSIONS
Qualitative differences between the idiopathic gating deficits observed in schizophrenic patients and AMPH-induced increases in T/C ratio in animals limit this models utility as a means of evaluating the ability of atypical antipsychotic drugs to restore normal sensory gating.
Joy
Brian
B
Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD 21228, USA.
McMahon
Robert P
RP
Shepard
Paul D
PD
D000661:Amphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005072:Evoked Potentials, Auditory / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D000661:Amphetamine; D003024:Clozapine