Amisulpride: From animal pharmacology to therapeutic action

Amisulpride is a benzamide derivative with a unique neurochemical and pschopharmacological profile. This compound has selective affinity for human dopamine D-3 and D-2 receptor subtypes in vitro (binding constant, K-i similar to 3 nmol/l) and blocks functional responses mediated by these receptors. In ex vivo binding studies, amisulpride is twice as selective for D, as for D, receptors. At low doses, it preferentially blocks presynaptic dopamine autoreceptors (increase in dopamine release in vivo in the rat olfactory tubercle, 50% effective dose, ED50 3.7 mg/kg), while postsynaptic dopamine receptor antagonism is apparent at higher doses (decrease in striatal acetylcholine levels, ED(50)similar to 60 mg/kg). Amisulpride preferentially stimulates dopamine synthesis and displaces H-3-raclopride binding in vivo in the limbic system rather than the striatum. It antagonizes apomorphine-induced hypothermia in mice and amphetamine-induced hypermotility in rats at low doses (ED50 2-3 mg/kg), blocks apomorphine-induced climbing and spontaneous grooming in mice, blocks apomorphine-induced gnawing in rats at higher doses (ED50 19-115 mg/kg) and does not induce catalepsy at 100 mg/kg. The preferential antagonism by amisulpride of presynaptic D,ID, receptors is reflected behaviourally in the potent blockade of apomorphine-induced effects mediated by dopamine autoreceptors (yawning and hypomotility: ED50 0.2 and 0.3 mg/kg, respectively) compared with those mediated by postsynaptic D-2 receptors (e.g, gnawing; ED50 115 mg/kg). Moreover, low doses of amisulpride induce prohedonic (potentiation of food-induced place preference) effects in rats. The atypical neurochemical and psychopharmacological profiles of amisulpride may explain its therapeutic efficacy on both positive and negative symptoms of schizophrenia.