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Vol. 280, Issue 1, 83-97, 1997
Synthélabo Recherche, CNS Research Department (H.S., Y.C.,
D.F., L.R., O.C., A.O., C.C., J.B., B.S.), Bagneux, France and
Centre
Hospitalier Lyon-Sud (K.C., F.G.), Pierre-Bénite, France
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 D2
(Ki = 2.8 nM) and D3
(Ki = 3.2 nM) receptors. Amisulpride shows
antagonist properties toward D3 and both pre- and
postsynaptic D2-like dopamine receptors of the rat striatum or nucleus accumbens in vitro. At low doses (
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 D2
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
D2/D3 antagonist [3H]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-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 D2 and
D3 receptor. In vivo, it displays a degree of
limbic selectivity and a preferential effect, at low doses, on dopamine
D2/D3 autoreceptors. This atypical profile may
explain the therapeutic efficacy of amisulpride in the treatment of
both positive and negative symptoms of schizophrenia.
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