A Rat Model of Sensory Integration Impairment for Therapeutic Drug Development: Autoradiographic Observations in Postmortem Brain

Thursday, May 17, 2012
Sheraton Hall (Sheraton Centre Toronto)
10:00 AM
A. Mahendra1, J. Skefos1, M. Ghulam2, E. Levin3 and M. Bauman1, (1)Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, (2)Boston University School of Medicine, Boston, MA, (3)Psychiatry & Behavioral Sciences, Duke Institute for Brain Sciences, Durham, NC
Background: Pre-pulse inhibition (PPI) is a process in which the motor response to a startling stimulus is inhibited by a less intense stimulus immediately preceding it. Diminished PPI represents one of the many sensory integration impairments observed in patients with schizophrenia and autism.

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.

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