Date of Defense

Spring 4-12-2000

Department

Biological Sciences

First Advisor

Leonard Ginsberg, Associate Dean of Arts & Sciences

Second Advisor

Montford F. Piercey, Pharmacia & Upjohn Company

Abstract

The goal of the project is to study U-101387G in more detail in schizophrenic rat models to better understand U-101387G and D4-specific antipsychotics. U-101387G is predicted to alleviate schizophrenic symptoms without any abnormal side effects Abnormal side effects include extrapyramidal symptoms (EPS) that resemble Parkinson's symptoms. Diagnostic areas of EPS include the nigrostriatal dopaminergic pathway, whereas, schizophrenic areas include the mesolimbic and mesocortical dopaminergic pathways. Haloperidol, a generic D2 blocker, was the first to be used to treat schizophrenia. Clozapine, a D4 receptor antagonist, has led to groundbreaking research in correlating schizophrenia, local cerebral glucose utilization, and D4 recptors. The D3 is thought to be the site of dopamine blockade during the scizophrenic state. Local cerebral glucose utilization in specified areas of the rat brain was used to show clozapine's effects on D4 receptors. EPS was eliminated by clozpine, but other abnormal effects prevent clozapine from becoming publicly available. U-101387G, developed as a D4-specific antipsychotic by the Pharmacia and Upjohn Company, is tested with haloperidol and amphetamine. Each drug dose was used at 1 mg/kg in Sokoloff's [14C]-2-deoxyglucose autoradiography and local cerebral glucose utilization technique on the male, albino rat. Of the 36 animals studied, the following combinations were tested: control, haloperidol(solo), U-101387G(solo), amphetamine(solo), haloperidol vs. amphetamine, and U-101387G vs. amphetamine. Results were detailed from image analysis, Sokoloff's equation, and ANOVA as statistical figures. Results reveal U-101387G's primary antagonist site on the mammillary body, but it may have an agonist role on the AV and VL thalami when vs. amphetamine. U-101387G, if proven effective experimentally, will be ready for the next step in the formulation process.

Comments

Cosigner: Erika Walker

Access Setting

Honors Thesis-Campus Only

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