Tardive dyskinesia develops in a substantial proportion of humans treated with chronic neuroleptics. Although some antipsychotic drugs may have a lessened propensity for inducing this disorder, it appears possible that all neuroleptics, if given in similar amounts for similar periods, will carry a substantial risk for inducing this syndrome. This has led clinicians to attempt to decrease the incidence of tardive dyskinesia by giving periodic drug-free intervals, or """"""""drug holidays"""""""". However, retrospective clinical studies are very unclear as to whether this practice is beneficial or actually deleterious, and animal studies suggest drug holidays can have either positive or negative effects depending upon precise experimental details. It is proposed here to study, using an animal model, what are the precise regimens of neuroleptic administration which facilitate or hinder the development of persisting side-effects of chronic neuroleptics. First we will perfect a method for conveniently delivering very constant levels of haloperidol to rats over prolonged periods of time and develop an automated procedure for precisely quantifying and identifying subcomponents of the """"""""vacuous chewing movements"""""""" which develop in rats administered chronic neuroleptics. Using these procedures the role of dosage and length of drug administration in determining the course of development of these abnormal oral behaviors and their persistance following drug discontinuation will be studied. It is then proposed to determine the exact experimental conditions under which """"""""drug holidays"""""""" in neuroleptic administration can have beneficial long-term effects. Included in these studies will be the determination of optimal drug holiday length, timing, and a comparison of abrupt versus gradual drug withdrawal. It is also proposed to determine whether there are differing degrees of persisting side-effects of chronic neuroleptics when these drugs are chronically administered so as to induce steady serum levels (as occur with depot injections) versus the more fluctuating levels induced by oral administration. 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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