The limbic functional selectivity of amperozide is not mediated by dopamine D2 receptors as assessed by in vitro and in vivo binding.

Behavioural, biochemical and electrophysiological studies suggest that amperozide affects mesolimbic dopamine neurotransmission. Amperozide is a potent 5-HT2, receptor antagonist with only a moderate affinity for rat brain dopamine D2 receptors. The brain regional dopamine D2 receptor binding properties of amperozide were investigated by using in vitro and in vivo radioligand binding techniques. Amperozide displaced [3H]spiroperidol binding from rat striatal and limbic dopamine D2 receptors with moderate affinity (Ki = 540 +/- 118 nM and Ki = 403 +/- 84 nM, respectively). The dopamine D2 receptor antagonist l-sulpiride and the agonist dopamine did not show different affinity in the two brain regions. Amperozide potently displaced in vivo [3H]spiroperidol binding in rat frontal cortex (ID50 = 1.4 mg/kg s.c.) but was devoid of effect in striatum, olfactory tubercle and nucleus accumbens (ID50 > 100 mg/kg s.c.). Chronic administration of amperozide (5 mg/kg p.o.) for three weeks did not result in any change of maximal dopamine D2 receptor number in either striatal or limbic tissue. The effects of amperozide on dopamine neurotransmission are thus not likely to occur by a direct interaction with dopamine D2 receptors in either striatal or limbic tissue. The functional limbic selectivity might rather be mediated by serotoninergic pathways.