Postsynaptic Dopamine D2 Receptors Research Articles

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.

Dopaminergic supersensitivity follows ferric chloride-induced limbic seizures

Injection of ferric chloride (FC) into the left amygdala of rats produced limbic seizures that lasted at least 3 weeks. In addition, FC-injected animals demonstrated motor impairment, decreased protesting vocalizations, and spontaneous stereotypies during a behavioral examination. An increase in apomorphine-induced stereotypies was also noted, and weekly administration of apomorphine for 3 weeks potentiated the increase in stereotypes produced by FC injection. These behavioral changes were associated with changes in postsynaptic dopamine D2 receptors. In animals injected only with FC, an increase in the [ 3H]-spiperone B max in the left nucleus accumbens and an increase in K d in the right nucleus accumbens were noted. In FC-injected animals challenged weekly with apomorphine for 3 weeks, increases in the [ 3H]-spiperone B max in both amygdalae, the left nucleus accumbens, and the right nucleus caudatus and increases in K d in the left amygdala and right nucleus accumbens were noted. Severance of the anterior commissure at the time of FC injection reversed most of these changes in behavior and dopamine receptor binding. Possible mechanisms for these changes are discussed, as well as the implications of these results for research on limbic dysfunction and psychopathology.