Chronic autoreceptor blockade and neuroleptic-induced dopamine receptor hypersensitivity

Metoclopramide and sulpiride, two benzamide compounds, are equally potent in terms of their ability to block postsynaptic D2 dopamine receptors. However these compounds show a marked divergence in their ability to block dopamine autoreceptors, as metoclopramide is 20-25-fold more potent than sulpiride in blocking these receptors. When injected twice daily for 16 days, metoclopramide at a dose of 10 mg/kg/day will result in the development a postsynaptic dopamine receptor hypersensitivity (i.e., increased behavioral response to apomorphine upon cessation of the chronic treatment). An equivalent dose and treatment schedule with sulpiride has no apparent effect on dopamine receptor sensitivity. Because of the divergent pre- and postsynaptic potency of these two drugs it was possible to construct an autoreceptor "dose response curve" by varying the amount of these two drugs injected. Combinations of these two drugs were chosen so that the level or amount of postsynaptic dopamine receptor blockade was held constant while the amount of dopamine autoreceptor blockade was gradually increased. The results of this autoreceptor blockade "dose response curve" indicated that chronic autoreceptor blockade was involved in the increased dopamine receptor sensitivity that develops upon withdrawal from the neuroleptic drugs. These results suggest that the blockade of dopamine autoreceptors, and perhaps the resulting increase in autoreceptor sensitivity, is an integral component of the neuroleptic-induced dopamine receptor hypersensitivity.