Schizophrenia is a complex disorder of unknown etiology. One prominent problem among schizophrenics is an inability to filter, or gate, sensory information. Normal individuals, when presented with identical paired stimuli (clicks), have a diminished midlatency auditory evoked potential the second click, as compared to the first click. They are said to be """"""""gating' their response to the second stimulus. By contrast, schizophrenics, and normal individuals administered psychotomimetics (amphetamine, PCP), have responses of similar magnitude to both clicks. Thus, they do not gate. This gating deficit has been successfully modeled in animals. Rats show a normal pattern of sensory gating which is altered to a schizophrenia-like loss of gating upon administration of psychotomimetic drugs. Recent clinical studies have demonstrated a transient normalization of sensory gating in schizophrenics following nicotine administration. Studies in the rat model have also implicated the nicotinic receptor, and a subtype of this receptor, the alpha-bungarotoxin binding site, in the modulation of sensory gating. Recently, several strains of inbred mice have been characterized which have differing numbers of alpha-bungarotoxin binding sites in the hippocampus. These mice offer an excellent model system in which to evaluate the nicotinic cholinergic mediation of sensory gating. The proposed studies will include pharmacologic manipulation, autoradiographic and in situ hybridization studies, breeding studies and development of a chronic recording model. In Experiment 1, the role of the hippocampal alpha-bungarotoxin binding site in sensory gating will be evaluated using anesthetized-preparation evoked potential recording coupled with injections of drugs effecting the alpha- bungarotoxin binding site. Hippocampal autoradiography for alpha- bungarotoxin binding and in situ hybridization for alpha7 mRNA will be performed on each recorded mouse. Experiment 2 will explore the role of the hippocampal classic nicotinic receptor in sensory gating in the same manner as Experiment 1. Drugs effecting the nicotinic receptor will be administered; autoradiography for the nicotinic receptor and in situ hybridization for alpha4 and beta2 mRNAs will be performed. Experiment 3 will address sensory gating and hippocampal muscarinic receptors using drugs active at this receptor, and autoradiographic visualization of hippocampal muscarinic binding. Experiment 4 will determine whether the manipulation of the number of hippocampal alpha-bungarotoxin binding sites will effect sensory gating. Both chronic pharmacologic intervention and breeding experiments will be performed. Autoradiography and in situ hybridization experiments will follow evoked potential recording. In Experiment 5, a chronic recording model in the mouse will be developed to permit multiple recording sessions in an awake and behaving mouse. Knowledge gained from the proposed research may help bridge the gap between clinical observation and specific neuronal and molecular abnormalities, and further, may aid in the development of new therapeutic approaches for schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29MH051931-01A1
Application #
2251427
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1994-07-01
Project End
1999-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Psychiatry
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Stevens, K E; Bullock, A E; Collins, A C (2001) Chronic corticosterone treatment alters sensory gating in C3H mice. Pharmacol Biochem Behav 69:359-66
Adams, C E; Stevens, K E; Kem, W R et al. (2000) Inhibition of nitric oxide synthase prevents alpha 7 nicotinic receptor-mediated restoration of inhibitory auditory gating in rat hippocampus. Brain Res 877:235-44
Stevens, K E; Kem, W R; Freedman, R (1999) Selective alpha 7 nicotinic receptor stimulation normalizes chronic cocaine-induced loss of hippocampal sensory inhibition in C3H mice. Biol Psychiatry 46:1443-50
Adams, C E; Stevens, K E (1998) Inhibition of nitric oxide synthase disrupts inhibitory gating of auditory responses in rat hippocampus. J Pharmacol Exp Ther 287:760-5
Stevens, K E; Kem, W R; Mahnir, V M et al. (1998) Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice. Psychopharmacology (Berl) 136:320-7
Stevens, K E; Nagamoto, H; Johnson, R G et al. (1998) Kainic acid lesions in adult rats as a model of schizophrenia: changes in auditory information processing. Neuroscience 82:701-8
Stevens, K E; Johnson, R G; Rose, G M (1997) Rats reared in social isolation show schizophrenia-like changes in auditory gating. Pharmacol Biochem Behav 58:1031-6
Stevens, K E; Freedman, R; Collins, A C et al. (1996) Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains. Neuropsychopharmacology 15:152-62