Tardive dyskinesia is a neurological disorder which sometimes develops after chronic or prolonged exposure to antipsychotic drugs. The disorder is characterized by abnormal movements, usually of the choreoathetotic or dystonic type, and may persist for many months or indefinitely even after withdrawal of the suspected causative agent. The actual underlying etiology of this disorder is unknown, but an increased sensitivity to dopamine in the basal ganglia is suspected. Understanding of the basic mechanisms underlying tardive dyskinesia is imperative for the development of a rational treatment or therapy. In the present proposal, the dopamine receptor response to the chronic presence of neuroleptics will be examined in laboratory rats. The quantitative technique of receptor autoradiography will be used so that the dopamine receptor populations in the mesolimbic system (which may be involved in the pathophysiology of schizophrenia) can be differentiated from the receptor populations in the nigrostriatal pathway (where these receptors could be involved in tardive dyskinesia). The actual response of the receptors (change in affinity or alteration in the number of receptors) to the chronic presence of the neuroleptic will be quantitated in each microscopic region; this type of study was not possible with pre-existing methodologies. Individual subtypes of dopamine receptors (D-1 and D-2) will be examined separately using newly developed, specific ligands (SCH 23390 and sulpiride, respectively). The changes observed in the rat brain will be compared to those which actually occur in the human, by examining the autoradiographic density, distribution and affinity of dopamine receptors in these same areas of human postmortem brain tissues from patients who died after suffering from well documented tardive dyskinesia. The functional relevance of these receptors will be examined by studying the metabolic alterations (2 deoxy-glucose utilization and adenylate cyclase activity) occurring in the treated animals vs. controls in response to a challenge with a dopaminergic agonist. These experiments will indicate how dopamine receptor regulation is altered during chronic dopamine receptor blockade and where these changes are occurring. The subtype of dopamine receptor involved, and the pathways involved in responding to the altered density or sensitivity will be compared to untreated controls in order to better understand the receptor mechanisms which may underlie tardive dyskinesia and thus contribute to a more rational approach to therapy.
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