The effects of dose and duration of neuroleptic administration on dopamine receptor sensitivity

It is well established that chronic treatment with neuroleptic agents which selectively block dopamine (DA) receptors in the brain leads to the development of DA receptor supersensitivity. However comparing the degree and duration of the changes in receptor sensitivity obtained by different investigators has been extremely difficult, because of the numerous differences that exist in individual methods of producing and examining DA receptor supersensitivity. By examining the DA receptor supersensitivity that ensues following chronic treatment with different doses and durations of pimozide, at various intervals after withdrawal from treatment, the overall parametric changes can be more directly compared. To measure the changes in DA receptor sensitivity following chronic pimozide treatment, both behavioral (d.-amphetamine-induced locomotor activity; apomorphine-induced stereotypy) and biochemical (DA receptor binding assay) techniques were utilized. With increasing doses of chronic pimozide treatment, the degree and duration of the resulting DA receptor supersensitivity increased as measured both behaviorally and biochemically. Similarily, the longer durations of chronic pimozide treatment had a greater effect on the degree and duration of the increased DA receptor sensitivity than did the shorter durations of treatment. Correlations were found between the biochemical and behavioral results both between groups of animals treated chronically with different doses and durations of pimozide and within individual groups of animals. In addition, the changes in receptor sensitivity following chronic pimozide treatment was due to an increase in the number of DA receptors with no change in the affinity of these receptors to DA. These results following chronic treatment with neuroleptics demonstrate that the behavioral supersensitivity observed in animals in response to either the direct DA agonist apomorphine or the indirect DA agonist d-amphetamine, may be a result of an increased number of DA receptors. Finally, the supersensitive DA receptors that develop as a result of chronic treatment with neuroleptics are discussed with regard to their possible relevance as an animal model of the iatrogenic disease, tardive dyskinesia, observed clinically in schizophrenic patients withdrawn from neuroleptic therapy.Medicine, Faculty ofGraduat