Tardive dyskinesia (TD) is a severe latrogenic disorder which develops gradually in schizophrenics treated with chronic neuroleptics. This laboratory has developed a highly unique animal model of tardive dyskinesia based upon a computerized system in which measures of oral movements (OMs) in rats are directly placed into computer memory together with the reports of human observers. The results obtained using this highly novel and rigorous approach are very different from those obtained using simple observational techniques, and suggest the best model of TD in rats is the tiny tremorous oscillations of the lips which rats begin to show only after many months of chronic neuroleptic administration and which are largely undetected by the naked eye. We now propose to further investigate this promising animal model of tardive dyskinesia by clarifying, through further computer analysis and amplified recording procedures, what the small oral oscillations actually represent. Other studies will access whether different regimens of neuroleptic administration alter the development of persistant side effects of chronic neuroleptics, including whether fluctuating or very steady levels of neuroleptics are more prone to induce the disorder. We also propose to compare the extent to which various classes of neuroleptics (including several novel, atypical neuroleptics) induce this disorder, and whether the concurrent administration of selected dopamine stimulants (D1 v. D2 agonists) facilitate or hinder the development of the syndrome. Other studies will further investigate the pharmacology of oral movements using drugs which act on dopamine, or acetylcholine, or GABA systems within the brain, and then compare effects of these compounds on TD-like vacuous OMs in chronic animals. Detailed regional, autoradiographic studies of receptor binding will be conducted on chronic neuroleptic animals at the completion of these experiments so that varying degrees of symptomatology can be correlated with regional alterations in brain biochemistry. These experiments address an important research issue involving a widespread iatrogenic disorder. The experimental questions addressed in this proposal will probably only be answered in the near future using an animal model such as that proposed here.
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