There exists a need for an animal model that would replicate some of the characteristics of the oral dyskinesias that occur in tardive dyskinesia, a long-lived motor abnormality that arises after excessive use of neuroleptic agents in humans. This model would be useful to investigate mechanisms that may be involved in tardive dyskinesia, and to test agents that have a potential to prevent or even reverse the motor or biochemical abnormalities that occur in tardive dyskinesia. Testing equipment is available for measuring the frequency of mouth openings, the amplitude of mouth movement, and the rates of mouth opening and closing. The technology uses frame grabbers to record the relative positions of upper to lower jaws at increments of 1/60 sec. With a computer assist, the data are recorded as amplitude of mouth opening vs. time. Fast fourier transformation provides an energy spectrum of the oral activity, so that comparison can be made with the low frequency mouth movements of tardive dyskinesia. The project is designed to set up this equipment in the laboratory to determine the oral characteristics of rats that have abnormal oral activity. We have found that there is a 10 fold increase in dopamine D2 antagonist-induced oral activity in adult rats that received a neonatal 6-hydroxydopamine lesion of the dopaminergic fibers in the brain. A similar enhancement of oral activity was produced by a Dl agonist in these rats. In this project we shall determine how the features of the oral activity in these and related models, compare with that shown for tardive dyskinesia. The Bmax and Kd for Dl and D2 receptors in the striatum will be determined, as well as the ratio of high and low affinity forms of each receptor type. Biochemical determination of the status of the receptor complex will be made for potentially useful models. The final study will explore the possible effects of a peptide that modulates the dopamine receptor, and which could possibly be useful in treatment of tardive dyskinesia. A new model to investigate aspects of tardive dyskinesia would be of immense value. The proposed model is of added benefit since the susceptibility for induction of oral activity is seemingly permanent.
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