NEUROCHEMICAL CHARACTERISTICS OF AMISULPRIDE, AN ATYPICAL DOPAMINE D-2 D-3 RECEPTOR ANTAGONIST WITH BOTH PRESYNAPTIC AND LIMBIC SELECTIVITY/

The benzamide derivative amisulpride shows a unique therapeutic profil e being antipsychotic, at high doses, and disinhibitory, at low doses, while giving rise to only a low incidence of extrapyramidal side effe cts. In vitro, amisulpride has high affinity and selectivity for the h uman dopamine D-2 (K-i = 2.8 nM) and D-3 (K-i = 3.2 nM) receptors. Ami sulpride shows antagonist properties toward D-3 and both pre- and post synaptic D-2-like dopamine receptors of the rat striatum or nucleus ac cumbens in vitro. At low doses (less than or equal to 10 mg/kg) amisul pride preferentially blocks presynaptic dopamine autoreceptors that co ntrol dopamine synthesis and release in the rat, whereas at higher dos es (40-80 mg/kg) postsynaptic dopamine D-2 receptor occupancy and anta gonism is apparent. In contrast, haloperidol is active in all of these paradigms within the same dose range. Amisulpride preferentially inhi bits in vivo binding of the D-2/D-3 antagonist [H-3]raclopride to the limbic system (ID50 = 17 mg/kg) in comparison to the striatum (ID50 = 44 mg/kg) of the rat, increases striatal and limbic tissue 3,4-dihydro xyphenylacetic acid levels with similar potency and efficacy, and pref erentially increases extracellular 3,4-dihydroxyphenylacetic acid leve ls in the nucleus accumbens when compared to the striatum. Haloperidol shows similar potency for the displacement of in vivo [H-3]raclopride binding in striatal and limbic regions and preferentially increases s triatal tissue 3,4-dihydroxyphenylacetic acid levels. The present data characterize amisulpride as a specific dopamine receptor antagonist w ith high and similar affinity for the dopamine D-2 and D-3 receptor. I n 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 tr eatment of both positive and negative symptoms of schizophrenia.