The Effect of A D3 Dopamine Antagonist and Phencyclidine (PDP) on Local Cerebral Glucose Utilization in the Rat Brain
McMichael, Amy E.
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Schizophrenia, which affects almost 1% of the world population, remains perhaps the most enigmatic diseases of the central nervous system. The most prominent biological theory describing schizophrenia's etiology is the "dopamine hypothesis" which suggests that schizophrenia is a result of hyperactivity of some central dopaminergic systems. Antipsychotics act to antagonize dopamine receptors and thus treat several of the symptoms, yet they produce a variety of side effects. It has been hypothesized that antipsychotics acting specifically at the recently discovered D3 dopamine receptor subtype, whose mRNA is predominantly located in mesolimbic pathways, may be effective at treating schizophrenia without producing extrapyramidal side effects. The 2-deoxyglucose (2-DG) autoradiography procedure of Sokoloff et ale (1977) was used to evaluate the effects of the 25-fold selective D3 dopamine antagonist U-99194A on local cerebral glucose utilization (LCGU) in the rat brain. U-99194A's effects were also studied in the phencyclidine (PCP) model of schizophrenia. PCP (5.0 mg/kg i.v.) increased brain energy metabolism in 27 of the 65 brain regions. Alone, U-99194A (10.0 mg/kg i.p.) had no effect on regional brain energy metabolism. When administered with PCP, U-99194A was able to antagonize the stimulatory effects of PCP in 12 of the brain regions examined. The majority of these brain regions were found in the cerebral cortex. Uviii 99194A was only able to partially antagonize PCP's stimulatory effects in the extrapyramidal regions. In addition, most of the structures that were stimulated by PCP in the thalamus and limbic regions were antagonized by U- 99194A. D3 antagonists, such as U-99194A, may therefore be effective in treating dopamine hyperactivity specifically in the mesolimbic pathways. Thus, this drug could be useful in treating the symptoms of schizophrenia without producing extrapyramidal side effects.With honors.