Article

Effects of acute and chronic clozapine on D-amphetamine-induced disruption of auditory gating in the rat

Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD 21228, USA.
Psychopharmacology (Impact Factor: 3.99). 08/2004; 174(2):274-82. DOI: 10.1007/s00213-003-1731-4
Source: PubMed

ABSTRACT 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.
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.
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.
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.
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.

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    • "Preclinical studies have attempted to delineate the neuronal pathways that mediate N40 gating and have implicated dopamine and glutamate (Adler et al., 1986; Swerdlow et al., 2006), GABA (Ma and Leung, 2011), noradrenaline (Adler et al., 1988; Keedy et al., 2007) and acetylcholine (Luntzleybman et al., 1992; Stevens et al., 1995). For example, drugs that increase dopamine receptor signalling, such as the dopamine releaser, amphetamine, disrupt N40 sensory gating (Adler et al., 1986), an effect which can be attenuated by antipsychotic drugs such as haloperidol and clozapine (Adler et al., 1988, 1986; Joy et al., 2004). Similarly, the glutamate NMDA receptor antagonist, phencyclidine, was shown to cause a disruption of N40 sensory gating (Adler et al., 1986; Swerdlow et al., 2006). "
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    • "The N40 wave demonstrates a diminished response to the test stimuli (T/C B 50%) in healthy controls (Miller et al. 1992) while disrupted gating has been shown in pharmacological models (e.g. following phencyclidine and amphetamine administration) of schizophrenia (Miller et al. 1992; Joy et al. 2004). An example of sensory gating is illustrated in Fig. 1, showing average auditory evoked LFPs recorded from the hippocampal CA3 region of an anesthetized rat. "
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