Amisulpride the 'atypical' atypical antipsychotic--comparison to haloperidol, risperidone and clozapine.

INTRODUCTION: Amisulpride's high and selective affinity for dopamine D2/3 (Ki 1.3/2.4 nM) receptors, lack of affinity for serotonin receptors, and its unusually high therapeutic doses (400-800 mg/day) makes it unique among atypical antipsychotics and prompted us to compare its actions with other antipsychotics in animal models.

METHODS: Amisulpride's effects on amphetamine and phencyclidine induced locomotor activity (AIL/PIL), conditioned avoidance response, catalepsy (CAT), subcortical Fos expression, and plasma prolactin was correlated to its time-course striatal D2/3 and prefrontal 5-HT2 receptor occupancy (D(2/3)/5-HT2RO); in comparison to haloperidol, clozapine, and risperidone.

RESULTS: Unlike the atypicals clozapine and risperidone, amisulpride lacked 5-HT2RO and showed a 'delayed' pattern of D2/3RO: 43, 60 and 88% after 1, 2 and 6 h (100 mg/kg), respectively, despite a quick onset (1 h) and decline (6 h) of prolactin elevation. While haloperidol and risperidone were effective at D2RO>60%, clozapine at D2/3RO<50%, amisulpride was effective only when its D2RO exceeded 60% with a delayed latency and lasted longer than other antipsychotics. CAT was observed for haloperidol and risperidone when D2RO exceeded 80%, while in the case of amisulpride, CAT was not observed even when doses exceeded 90% D2/3RO. Amisulpride also displayed functional limbic selectivity in Fos expression like the other atypicals.

CONCLUSIONS: Amisulpride's "delayed" functional profile on acute administration and the need for high doses is most likely due to its poor blood-brain-barrier penetration; however, it is distinct from other atypicals in showing low motor side-effects, activity against phencyclidine, and a mesolimbic preference, despite no action on serotonin receptors.