Schizophrenia, a chronic mental disorder with both genetic and environmental origins, is a major world health problem affecting up to 1% of the population regardless of culture or geographic location. Dysfunctions in brain dopamine systems are implicated in the symptoms, and amphetamine, a drug that stimulates brain dopamine activity, can produce a schizophrenia-like psychosis in humans. Antipsychotic drugs ameliorate the symptoms of spontaneously occurring and amphetamine-induced schizophrenia, but cause bothersome side effects and have limited efficacy. Hence, the search for side-effect-free antipsychotics continues. The purpose of the proposed work is to accelerate drug research by introducing a new method and a newly discovered phenomenon to this research arena. The new method is the force-plate actometer, an instrument that quantifies behavior with high temporal and spatial resolution. The new discovery involves the rhythmic pattern of amphetamine-induced focused stereotypies in rats, a long used, but heretofore poorly quantified, laboratory model for evaluating antipsychotic drug potential. We now know that the focused stereotypies are characterized by sustained, precisely regulated, 10-Hz rhythmic head movements while the rat remains immobile. Our data indicates that the atypical antipsychotic drug clozapine slows the amphetamine-induced rhythm without restoring locomotion, while other drugs have distinctly different profiles. The 4 specific aims are: 1) to determine if other atypical antipsychotic drugs have the clozapine-like rhythm-slowing property in the amphetamine-treated rat; 2) to use selective pharmacological tools to reduce which neurotransmitter receptor systems participate in the rhythm control; 3) to establish the generality of the 10-Hz rhythm and its modulation by clozapine in genetically distinct rats strains; and 4) to use an operant-force-plate hybrid instrument to measure the ability of the antipsychotic drugs to restore learned, adaptive behavior disrupted by amphetamine and to quantify concurrently motor side effects produced by the antipsychotic drugs. The results will improve our understanding of the pharmacological basis of dopamine related behaviors and assist in the discovery of improved antipsychotic medications.
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