Intermittent versus continuous central administration of clozapine in DBA/2 mice, improvement in sensory inhibition deficits

Deficient sensory inhibition, the failure to inhibit responses to repeated stimuli, is a hallmark of schizophrenia, and is thought to be related to difficulties with attention and working memory. Sensory inhibition is assessed by comparing the auditory-evoked EEG responses to 2 closely-spaced identical stimuli. Normal individuals show suppressed response to the second stimulus while schizophrenia patients have responses of similar magnitude to both stimuli. This deficit has been linked to polymorphisms in the promoter for the α7 nicotinic receptor gene, resulting in reduced numbers of receptors on hippocampal interneurons. This deficit is modeled in DBA/2 mice which also show a polymorphism in the promoter for the α7 nicotinic receptor gene and reduced numbers of hippocampal α7 receptors. Systemic administration of clozapine, the most efficacious antipsychotic medication, improves sensory inhibition deficits in both schizophrenia patients and DBA/2 mice. We have previously shown that acute intracerebroventricular (ICV) injections of clozapine induced similar improvement in sensory inhibition in DBA/2 mice. Here we demonstrate the efficacy of chronic ICV clozapine administration in improving sensory inhibition in DBA2 mice. Mice received ICV vehicle, 3, 7.5, 15 or 30 μg of clozapine, either continuously or as a once-per-day injection. Mice were recorded on the 7th day of drug delivery. Both approaches produced improved sensory inhibition, but the daily bolus injection was effective at a lower dose (3 μg/day) than the continuous delivery (15 μg/day). The bolus injections also showed significant improvement up to 36 h post injection thus suggesting that this approach may be more efficacious.