The effects of dose and duration of chronic pimozide administration on dopamine receptor supersensitivity.

Abstract

The neuroleptic drug pimozide was administered chronically to rats at different doses (0.75, 1.5 or 3.0 mg/kg, twice daily for 10 days) or for different durations (1.5 mg/kg twice daily for 5, 10, 20 or 40 days). At various intervals (4-40 days) after withdrawal dopamine (DA) receptor density in the striatum was assessed directly using specific [3H]-spiroperidol binding and indirectly by means of apomorphine-induced stereotypy and amphetamine-induced locomotor activity. The increase in the density of DA receptors was shown to be dependent upon the dose but not upon the duration of chronic pimozide. In contrast, the enhanced apomorphine-induced stereotypy was influenced by the duration but not by the dose of chronic pimozide. The potentiation of d-amphetamine-induced locomotor activity was found to vary as a function of both dose and duration of chronic pimozide administration. The results indicate that the augmentation of these apomorphine- and amphetamine-induced behaviors cannot be attributed solely to striatal DA receptor supersensitivity and that other, presently unspecified factors must contribute. It is also argued that in the absence of pharmacologically-induced DA receptor stimulation, the functional consequences of neuroleptic-induced increases in the density of striatal DA receptors are not apparent and remain unknown. In addition, these findings support the view that neuroleptic-induced proliferation of DA receptors cannot be the sole mechanism underlying tardive dyskinesia in man.