Tardive dyskinesia (TD) develops gradually in schizophrenics given chronic neuroleptics. Rodent models of TD are highly controversial. This laboratory has developed a very unique rat model of TD based on a computerized system whereby measures of oral movements (OMs) in rats are directly placed into computer memory together with the reports of human observers. Using this model, we have demonstrated an artifact related to activity levels in the test used by other laboratories, one that can lead to spuriously inflated oral movement scores and which may help to clarify this controversial field. We have found that rats treated with continuously administered """"""""typical"""""""" neuroleptics do not necessary develop more oral movements per se, but rather gradually develop OMs which have an altered and abnormal form, most notably increased energy at 1-2 Hz. This is an important finding, for this is precisely the altered energy spectrum reported in humans with TD. We have further found that a completely different, """"""""primed dystonia"""""""" syndrome (large amplitude, rapid (4-7 Hz), gaping OMs) develops in rats given comparable neuroleptics but in a highly fluctuating regimen (once per week large injections). While """"""""atypical"""""""" neuroleptics (clozapine and raclopride) do not induce these syndromes, with clozapine it seems that the TD-like profile gradually develops but its expression is inhibited. Studies of a variety of brain receptors demonstrate persisting altered D2 and GABA receptors in these animals, but similar changes are observed following continuous and intermittent HAL, i.e. in rats which manifest completely different behavioral syndromes. Rats treated with these chronic neuroleptics also gradually develop very small OMs, so small that only the computer can detect them, an effect which deserves further investigation. We propose to pursue this model, which we argue is presently the best viable rodent model of neuroleptic-induced oral dyskinesias, by studying how drugs which affect dopamine or cholinergic receptors, as well as other pharmacological agents, alter the form and frequency of the two neuroleptic-induced oral syndromes. We further propose studies designed to map the underlying brain circuitry, attempting to determine the location of the altered pattern generator using local injections of agonists or discrete brain lesions. Other studies will study effects of aging and atypical neuroleptics. We also propose to determine whether other syndromes reported in humans also develop in these rats, such as an akathisia-like inability to remain still, and if rats also develop the """"""""primed dystonia"""""""" syndrome reported in primates. In addition, recordings from humans with TD will be collected and the rom of their movements compared to those from rats administered similar drugs. These experiments address an important research issue involving a widespread iatrogenic disorder; the questions addressed will probably only be answered using a model such as that proposed here. They are of unusual clinical significance, but also represent a basic advance in scientific technology, for the computerized techniques we have developed for the measurement of behavior represent a highly evolved analysis system.
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