title: Psychopharmacological profile of amisulpride: an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity.
abstract: Amisulpride, a benzamide derivative, is an antipsychotic drug with a pharmacological profile distinct from that of classical neuroleptics such as haloperidol and from that of another benzamide, remoxipride. In mice, amisulpride antagonized hypothermia induced by apomorphine, quinpirole or (+/-) 7-hydroxy-2-(di-n-propylamino)-tetralin, an effect involving D2/D3 receptors, at similar doses (ED50 approximately 2 mg/kg i.p.), which were much lower than doses that blocked apomorphine-induced climbing, an effect involving postsynaptic D2 and D1 receptor activation (ED50 = 21 mg/kg i.p.). Much higher doses (ED50 = 54 mg/kg i.p.) of amisulpride were needed to block grooming behavior observed after a short period in water, a D1 receptor-mediated behavior. In rats, amisulpride preferentially inhibited effects produced by low doses of apomorphine (hypomotility and yawning), related to stimulation of presynaptic D2/D3 dopamine autoreceptors (ED50 = 0.3 and 0.19 mg/kg i.p.). By contrast, amisulpride antagonized apomorphine-induced hypermotility, a postsynaptic dopamine receptor-mediated effect, at a much higher dose (ED50 = 30 mg/kg i.p.). Amisulpride (100 mg/kg i.p.) only partially inhibited apomorphine-induced stereotypies (gnawing) and had no effect on stereotypies induced by d-amphetamine. However, d-amphetamine-induced hyperactivity was antagonized by doses of amisulpride as low as 3 mg/kg i.p., which may indicate selectivity of this drug for limbic dopaminergic mechanisms. In addition, in contrast to haloperidol or remoxipride, which produced catalepsy at doses 2 or 3 times higher than those that antagonized stereotypies induced by apomorphine, amisulpride did not induce catalepsy up to a dose of 100 mg/kg i.p., which occupies 80% of striatal D2 receptors. This pharmacological profile of amisulpride, characterized by a preferential blockade of effects involving presynaptic mechanisms and limbic structures, may explain the clinical efficacy of this drug against both negative and positive symptoms of schizophrenia and its low propensity to produce extrapyramidal side effects.
authors.affiliation: Synthélabo Recherche, CNS Research Department, Bagneux, France.
authors.forename: G
authors.initials: G
authors.lastname: Perrault
authors.forename: R
authors.initials: R
authors.lastname: Depoortere
authors.forename: E
authors.initials: E
authors.lastname: Morel
authors.forename: D J
authors.initials: DJ
authors.lastname: Sanger
authors.forename: B
authors.initials: B
authors.lastname: Scatton
mesh_terms: D000077582:Amisulpride; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D003913:Dextroamphetamine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D006120:Grooming / Q000187:drug effects; D008032:Limbic System / Q000187:drug effects*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3; D017661:Receptors, Presynaptic / Q000187:drug effects*; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493594:Drd3 protein, mouse; C493595:Drd3 protein, rat; D050637:Receptors, Dopamine D3; D017661:Receptors, Presynaptic; D013469:Sulpiride; D000077582:Amisulpride; D001058:Apomorphine; D003913:Dextroamphetamine