ANTISTEREOTYPIC EFFECTS OF DOPAMINE D-1 AND D-2 ANTAGONISTS AFTER INTRASTRIATAL INJECTION IN RATS - PHARMACOLOGICAL AND REGIONAL SPECIFICITY
ANTISTEREOTYPIC EFFECTS OF DOPAMINE D-1 AND D-2 ANTAGONISTS AFTER INTRASTRIATAL INJECTION IN RATS - PHARMACOLOGICAL AND REGIONAL SPECIFICITY
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DOI：
10.1007/bf00499901
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发表时间：
1985-01-01
影响因子：
3.6
通讯作者：
ARNT, J
中科院分区：
文献类型：
--
作者：
ARNT, J
研究了一系列多巴胺（DA）拮抗剂在脑内和外周注射后的阿扑吗啡拮抗作用。在腹侧纹状体内用D-1拮抗剂（SCH 23390）、D-2拮抗剂（苯甲酰胺类、丁酰苯酮类）和混合的D-1/D-2拮抗剂（噻吨类、吩噻嗪类）选择性地发现抑制活性，而α-D-1拮抗剂（SCH 23390）、D-2拮抗剂（苯甲酰胺类、丁酰苯酮类）和混合的D-1/D-2拮抗剂（噻吨类、吩噻嗪类）选择性地发现抑制活性。肾上腺素受体拮抗剂、毒蕈碱和5-羟色胺S2拮抗剂无效。观察到绝对效力和外周与纹状体内效力比的巨大差异。发现亲水性化合物（-）-舒必利、维拉利必利和多潘立酮具有高外周与中枢选择性比和高纹状体内效力，这些化合物不易穿过血脑屏障。还观察到苯甲酰胺、YM 09151-2、氟哌啶醇和螺哌啶醇的高纹状体内效力，尽管这些化合物具有较低的外周与纹状体内选择性比率。脑内给药后，抗精神病药的效力并不完全取决于DA受体的亲和力，但另外对理化性质。外周与纹状体内的效力比的基础上，它的结论是，在这项研究中，只有少数的神经抑制剂测试是适合于地形研究DA受体功能使用脑内注射，但（-）-舒必利是一个例子结合高效力，高中枢选择性，高DA D-2受体特异性，立体选择性和长期的行动。以（-）-舒必利为模型化合物，进一步研究了阿扑吗啡拮抗作用的位点选择性。对口腔刻板的抑制活性被优先注入腹侧纹状体后发现，而低组件模式的阿扑吗啡刻板（嗅，饲养，运动）被阻止同样好，在腹侧纹状体和神经核。相反，（-）-舒必利诱导背侧纹状体的口腔刻板症的促进。在额叶皮质、膝上皮质、隔区、杏仁核、黑质或丘脑注射阿扑吗啡后，未发现对阿扑吗啡刻板性的影响。这些结果支持了在损伤研究中获得的数据，表明腹侧纹状体是DA受体阻断后介导抑制口腔刻板症的重要部位。然而，纹状体和纹状体之间的分化，在调解刻板和多动症是不是绝对的，因为已经提出的损害研究。
Apomorphine antagonistic effects of a range of dopamine (DA) antagonists were studied after intracerebral and after peripheral injection. Inhibitory activity was found selectively within the ventral striatum with a D-1 antagonist (SCH 23390), D-2 antagonists (benzamides, butyrophenones) and mixed D-1/D-2 antagonists (thioxanthenes, phenothiazines), whereas .alpha.-adrenoceptor antagonists, muscarinic- and serotonin S2-antagonists were ineffective. Great differences in absolute potencies and in peripheral versus intrastriatal potency ratios were observed. High peripheral versus central selectivity ratios and high intrastriatal potencies were found with the hydrophilic compounds (-)-sulpiride, veralipride and domperidone which do not readily cross the blood-brain barrier. High intrastriatal potency was also observed for the benzamide, YM 09151-2, haloperidol and spiroperidol although these compounds had lower peripheral versus intrastriatal selectivity ratios. Neuroleptic potency after intracerebral administration did not depend solely on DA receptor affinity but additionally on physicochemical properties. On the basis of the peripheral vs. intrastriatal potency ratios, it is concluded that only few of the neuroleptics tested in this study are suited for topographical studies of DA receptor function using intracerebral injection but that (-)-sulpiride is one example combining high potency, high central selectivity, high DA D-2 receptor specificity, stereoselectivity and long duration of action. The site-selectivity of apomorphine-antagonistic effects was further studied using (-)-sulpiride as a model compound. Inhibitory activity against oral stereotypy was preferentially found after injection into the ventral striatum, whereas the low-component patterns of apomorphine stereotypy (sniffing, rearing, motility) were blocked equally well in the ventral striatum and nucleus accumbens. In contrast, a facilitation of oral stereotypy was induced by (-)-sulpiride in the dorsal striatum. No effect on apomorphine-stereotypy was found after injection into frontal cortex, supragenual cortex, septum, amygdala, substantia nigra or thalamus. These results support data obtained in lesion studies indicating the ventral striatum as the important site mediating inhibition of oral stereotypy after DA receptor blockade. However, the differentiation between striatum and accumbens in mediation of stereotypy and hyperactivity was not as absolute as has been suggested by lesion studies.