Objectives: The objective of our project is to explore potential neuropharmacological mechanisms of clozapine-mediated PPI improvement.
Methods: In the current study 36 female Sprague-Dawley rats were used to study mixed-modal PPI with an acoustic prepulse and a tactile (air-puff) startling stimulus. Animals were chronically administered via osmotic minipump the NMDA glutamate receptor antagonist, dizocilpine (0.15 mg/kg/day), the H1 histamine receptor antagonist, pyrilamine (50 mg/kg/day), the combination of the two drugs or the saline vehicle (N=9/group). Following the completion of these psychopharmacological studies, we performed postmortem radioligand assays on histological sections to determine behaviorally relevant shifts in H1 receptor and nicotinic acetylcholine receptor binding within five brain regions in these animals: the hippocampus, amygdala, superior and inferior colliculi, and the anterior cingulate cortex.
Results: During the first week of administration pyrilamine caused a significant (p < 0.025) main effect of improving PPI. There was no indication of lessening of this effect with dizocilpine co-exposure. The addition of pyrilamine to dizocilpine treatment significantly (p < 0.025) improved PPI relative to dizocilpine alone.
Conclusions: H1 receptor antagonism is one of the proposed therapeutic mechanisms of the atypical antipsychotic drug clozapine, which has marked H1 antagonistic effects. These results implicate attenuation of histaminergic transmission within the anterior cingulate and heightened acetylcholine transmission in the limbic system as an important focus of further study into treatment for disorders of sensory integration and behavioral inhibition.