Date of Defense
John Spitsbergen, Biological Sciences
Montford Piercey, Pharmacia & Upjohn
Leonard Beuving, Biological Sciences
The most accepted explanation of the cause of schizophrenia is the dopamine hypothesis of schizophrenia. The dopamine hypothesis of schizophrenia states that excessive dopamine (DA) located in the mesolimbic and mesocortical dopamine systems of the brain is the cause of the disease symptoms. Sokoloff et al. have predicted that D3 antagonists may be able to offer schizophrenics relief from some of their symptomology by selectively binding to DA receptors located in the mesolimbic and mesocortical dopaminergic systems(3). This experiment used the 2-deoxyglucose method (2-DG) as developed by Sokoloff et al. to evaluate the ability of U-142043A, a a D3 antagonist, to antagonize amphetamine(AMP) induced increases in local cerebral glucose utilization(LCGU) (28). The main findings in this experiment were that U-142043A caused mass decreases in LCGU. Although the main ability of U-142043A to reverse AMP induced increases in brain metabolism, this goal was not achieved due to a lack of AMP induced increases in brain metabolism as compared to control In previous experiments at Pharmacia & Upjohn(PNU) AMP has shown inconsistent results in stimulating LCGU in rats (Unpublished studies PNU). In previous experiments at Pharmacia & Upjohn when AMP stimulation was seen it was in experiments where the control rats had lower cerebral glucose brain metabolism as compared to control groups of experiments which did not show significant AMP stimulation (Unpublished study PNU). In this experiment it is possible that the intraperitoneal cannula used to deliver the U-142043A or a control of saline may have been irritating to the rats causing their brain metabolism to increase and thus preventing the observation of further increases in brain metabolism induced by AMP. Amphetamine did cause stimulation of brain metabolism in some regions and in some of these regions antagonism of AMP induced increases in LCGU were seen. Reversal of AMP induced increases in LCGU were seen in the globus pallidus, substantia nigra pars compacta and the vestibular nuclei. However, the observation of the reversal of AMP induced stimulation of glucose metabolism in the structures seen in this experiment is inconsistent with that a D3 antagonist is predicted to do.
Lougen, Martin T. Jr., "The Effects of U-142043A upon Local Cerebral Glucose Utilization in Rats" (1997). Honors Theses. 212.
Honors Thesis-Campus Only