Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity.
Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity.
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发表时间：
1997
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通讯作者：
H. Schoemaker;Y. Claustre;D. Fage;L. Rouquier;K. Chergui;O. Curet;A. Oblin;F. Gonon;C. Carter;J. Benavides;B. Scatton
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作者：
H. Schoemaker;Y. Claustre;D. Fage;L. Rouquier;K. Chergui;O. Curet;A. Oblin;F. Gonon;C. Carter;J. Benavides;B. Scatton
苯甲酰胺衍生物氨磺必利显示出独特的治疗特性，在高剂量下为抗精神病药，在低剂量下为去抑制药，同时仅产生低发生率的锥体外系副作用。在体外，氨磺必利对人多巴胺D2（Ki = 2.8 nM）和D3（Ki = 3.2 nM）受体具有高亲和力和选择性。氨磺必利对D3和突触前和突触后的D2样多巴胺受体的大鼠纹状体或核在体外表现出拮抗剂特性。在低剂量（≤ 10 mg/kg）下，氨磺必利优先阻断控制大鼠多巴胺合成和释放的突触前多巴胺自身受体，而在较高剂量（40-80 mg/kg）下，突触后多巴胺D2受体占据和拮抗作用明显。相比之下，氟哌啶醇在相同剂量范围内在所有这些范例中均具有活性。氨磺必利优先抑制D2/D3拮抗剂[3 H]雷氯必利与边缘系统的体内结合（ID 50 = 17 mg/kg）与纹状体相比（ID 50 = 44 mg/kg），以类似的效力和功效增加纹状体和边缘组织3，4-二羟基苯乙酸水平，并优先增加细胞外3，与纹状体相比，中脑核中的4-二羟基苯乙酸水平。氟哌啶醇在体内纹状体和边缘区[3 H]雷氯必利结合的置换方面表现出相似的效力，并优先增加纹状体组织3，4-二羟基苯乙酸水平。本数据将氨磺必利表征为特异性多巴胺受体拮抗剂，对多巴胺D2和D3受体具有高且相似的亲和力。在体内，它表现出一定程度的边缘系统的选择性和优先的效果，在低剂量下，多巴胺D2/D3自动受体。这种非典型性特征可以解释氨磺必利治疗精神分裂症阳性和阴性症状的疗效。
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 (< or = 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.