Biochemical and pharmacological differentiation of neuroleptic effect on dopamine D-1 and D-2 receptors.
Biochemical and pharmacological differentiation of neuroleptic effect on dopamine D-1 and D-2 receptors.
复制标题
抗精神病药物对多巴胺 D-1 和 D-2 受体作用的生化和药理学差异。
DOI：
10.1007/978-3-7091-4408-4_15
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发表时间：
1983
期刊：
影响因子：
--
通讯作者：
A. V. Christensen
中科院分区：
文献类型：
--
作者：
J. Hyttel;A. V. Christensen
在多巴胺（DA）受体结合试验中，可以测量两种不同的受体群体。以~ 3 H-氟哌啶醇或~ 3 H-螺哌啶醇为配体检测D-2受体。当噻吨类神经抑制剂3 H-顺式（Z）-氟噻吨或3 H-吡氟噻吨用作配体时，可以检测到与腺苷酸环化酶偶联的D-1受体。在置换实验中，丁酰苯（氟哌啶醇和螺哌啶）和二苯基丁基哌啶（匹莫齐特）仅与D-2受体相互作用，而噻吨（顺[Z]-氟噻吨、顺[Z]-匹氟噻吨和顺[Z]-氯噻吨）对D-1和D-2受体具有相同的亲和力。在行为研究中也可以看到类似的差异。通过与抗胆碱能药物或GABA激动剂同时治疗，可显著减弱丁酰苯酮和二苯基丁基哌啶的哌甲酯拮抗作用。噻吨的效果几乎没有变化。当小鼠用精神抑制剂治疗12天时，诱导对哌甲酯的超敏感性。超灵敏度被噻吨逆转，而丁酰苯和二苯基丁基哌啶根本没有影响。这些差异似乎不是由于对DA受体亲和力的改变，因为顺式（Z）-氟哌噻吨、氟哌啶醇、DA或阿朴吗啡置换3 H-吡氟噻吨或3 H-螺哌啶醇的能力在超敏小鼠和对照小鼠中是相同的。结果清楚地表明，作用于D-1和D-2受体的精神抑制剂具有与仅作用于D-2受体的精神抑制剂不同的行为特征。
In dopamine (DA) receptor binding tests two different receptor populations can be measured. By using 3H-haloperidol or 3H-spiroperidol as ligands D-2 receptors are detected. When the thioxanthene neuroleptics 3H-cis (Z)-flupenthixol or 3H-piflutixol are used as ligands D-1 receptors coupled to adenylate cyclase can be detected. In displacement experiments butyrophenones (haloperidol and spiroperidol) and diphenylbutylpiperidines (pimozide) interact with D-2 receptors only, whereas thioxanthenes (cis [Z]-flupenthixol, cis [Z]-piflutixol and cis [Z]-clopenthixol) have equal affinity for D-1 and D-2 receptors. A similar differentiation is also seen in behavioral studies. The methylphenidate antagonistic effect of butyrophenones and diphenylbutylpiperidines is dramatically attenuated by concomitant treatment with an anticholinergic agent or a GABA agonist. The effect of thioxanthenes is almost unchanged. When mice are treated for 12 days with neuroleptics, supersensitivity to methylphenidate is induced. The supersensitivity is reversed by thioxanthenes, whereas butyrophenones and diphenylbutylpiperidines have no effect at all. These differences do not appear to be due to a change in the affinity for DA receptors because the ability of cis (Z)-flupenthixol, haloperidol, DA or apomorphine to displace 3H-piflutixol or 3H-spiroperidol is the same in supersensitive and control mice. The results clearly demonstrate that neuroleptics acting on both D-1 and D-2 receptors have a behavioral profile different from that of neuroleptics acting exclusively on D-2 receptors.