Differential Alteration of Striatal D-1 and D-2 Receptors Induced by the Long-Term Administration of Haloperidol, Sulpiride or Clozapine to Rats

Abstract

Rats received haloperidol, sulpiride, or clozapine in their daily drinking water for up to 1 year in clinically equivalent doses. After 12 months’ drug intake, and while drug administration continued, striatal dopamine function was assessed. Haloperidol induced D-2 receptor hypersensitivity as shown by enhanced apomorphine-induced stereotypy, elevated B_max for specific ³H-spiperone and ³H-NPA binding, and an increase in striatal acetylcholine content. D-1 receptor sites appeared unaffected, since dopamine-stimulated adenylate cyclase and specific ³H-piflutixol binding were not altered. In contrast, neither sulpiride nor clozapine enhanced apomorphine-induced stereotypy or increased B_max for ³H-spiperone binding. Sulpiride, but not clozapine, increased B_max for ³H-NPA binding; clozapine, but not sulpiride, elevated striatal acetyl choline concentrations. In general, both sulpiride and clozapine enhanced D-1 function as assessed by dopamine-stimulated adenylate cyclase or ³H-piflutixol binding. On acute administration sulpiride and clozapine appear to act at D-2 sites, but continuous chronic administration of these compounds does not result in the development of striatal D-2 receptor hypersensitivity. The absence of change in D-2 function during chronic treatment, coupled with an ability to enhance D-1 function, may contribute to the low incidence of tardive dyskinesia produced by these drugs in man.

This study was supported by the Wellcome Trust, the Medical Research Council and the Research Funds of the Bethlem Royal and Maudsley Hospitals and King’s College Hospital