Amisulpride the ‘atypical’ atypical antipsychotic — Comparison to haloperidol, risperidone and clozapine

Abstract 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 (D2/3 /5-HT2 RO); in comparison to haloperidol, clozapine, and risperidone. Results Unlike the atypicals clozapine and risperidone, amisulpride lacked 5-HT2 RO and showed a ‘delayed’ pattern of D2/3 RO: 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 D2 RO > 60%, clozapine at D2/3 RO < 50%, amisulpride was effective only when its D2 RO exceeded 60% with a delayed latency and lasted longer than other antipsychotics. CAT was observed for haloperidol and risperidone when D2 RO exceeded 80%, while in the case of amisulpride, CAT was not observed even when doses exceeded 90% D2/3 RO. 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.