Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity
Schoemaker, H.; Claustre, Y.; Fage, D.; Rouquier, L.; Chergui, K.; Curet, O.; Oblin, A.; Gonon, F.; Carter, C.; Benavides, J.; Scatton, B.
Journal of Pharmacology and Experimental Therapeutics 280(1): 83-97
1997
ISSN/ISBN: 0022-3565 PMID: 8996185 Document Number: 478864
The benzamide derivative amisulpride shows a unique therapeutic profile being antipsychotic, at high doses, and disinhibitory, at low doses, while giving rise to only a low incidence of extrapyramidal side effects. In vitro, amisulpride has high affinity and selectivity for the human dopamine D-2 (K-i = 2.8 nM) and D-3 (K-i = 3.2 nM) receptors. Amisulpride shows antagonist properties toward D-3 and both pre- and postsynaptic D-2-like dopamine receptors of the rat striatum or nucleus accumbens in vitro. At low doses ( ltoreq 10 mg/kg) amisulpride preferentially blocks presynaptic dopamine autoreceptors that control dopamine synthesis and release in the rat, whereas at higher doses (40-80 mg/kg) postsynaptic dopamine D-2 receptor occupancy and antagonism is apparent. In contrast, haloperidol is active in all of these paradigms within the same dose range. Amisulpride preferentially inhibits in vivo binding of the D-2/D-3 antagonist (3H)raclopride to the limbic system (ID-50 = 17 mg/kg) in comparison to the striatum (ID-50 = 44 mg/kg) of the rat, increases striatal and limbic tissue 3,4-dihydroxyphenylacetic acid levels with similar potency and efficacy, and preferentially increases extracellular 3,4-dihydroxyphenylacetic acid levels in the nucleus accumbens when compared to the striatum. Haloperidol shows similar potency for the displacement of in vivo (3H)raclopride binding in striatal and limbic regions and preferentially increases striatal tissue 3,4-dihydroxyphenylacetic acid levels. The present data characterize amisulpride as a specific dopamine receptor antagonist with high and similar affinity for the dopamine D-2 and D-3 receptor. In vivo, it displays a degree of limbic selectivity and a preferential effect, at low doses, on dopamine D-2/D-3 autoreceptors. This atypical profile may explain the therapeutic efficacy of amisulpride in the treatment of both positive and negative symptoms of schizophrenia.