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CLOZAPIN--CHOLINERGIC BASIS OF MESOLIMBIC SPECIFICITY

氯氮平--中脑边缘特异性的胆碱能基础

基本信息

批准号：
3428725
负责人：
ELIOT L GARDNER
金额：
$ 4.66万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-09-30 至 1989-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3428725
关键词：
anticholinergic agent brain electronic stimulator clozapine dopamine receptor drug screening /evaluation laboratory rat limbic system psychotropic drugs receptor sensitivity schizophrenia self stimulation tranquilizer

项目摘要

The objective of this research is to gain insight into brain mechanisms of action of the clinically atypical antipsychotic drug clozapine. Unique among anti-schizophrenic drugs, clozapine produces virtually no extrapyramidal side effects or tardive dyskinesia, the often-serious neurological side effects common to other antipsychotic drugs which are thought to result from antipsychotic drug-induced dysfunction in the nigrostriatal dopamine (DA) system. A large body of research, both from this laboratory and elsewhere, strongly suggests that clozapine selectively acts as a functional DA antagonist in the mesolimbic DA system while virtually sparing the nigrostriatal system. This site-specificity explanation of clozapine's unique pharmacological profile is attractive on many grounds, not the least of which is the fact that current pharmacological methods for screening potential new antipsychotic drugs (which do not presently distinguish between mesolimbic and nigrostriatal specificities) could be modified to select only compounds having site-specific mesolimbic profiles. To this end, we have developed an adaptation of the electrical intracranial self-stimulation (ICSS) paradigm which is highly accurate in distinguishing clozapine's mesolimbic site-specificity from the more anatomically diffuse DA antagonism of classical neuroleptics. The paradigm used for these studies, and to be used for the present work, is that of chronic neuroleptic-induced functional DA hypersensitivity in both mesolimbic and nigrostriatal DA loci as assessed by the ICSS model. We now seek funds to extend our previous work by addressing the following question - is clozapine's mesolimbic functional stie-specificity a result of clozapine's powerful intrinsic anticholinergic potency? If "yes", development of new antischizophrenic agents with clozapine-like intrinsic anticholinergic potency would appear warranted. If "no", clozapine's unique atypical profile must logically derive from other neuropharmacological mechanisms, possibly including differential action on mesolimbic versus nigrostriatal presynaptic modulatory mechanisms. Also, if "no", the utility of the ICSS paradigm for screening potential new antipsychotic drugs would be immense, since it would not detect "false-positive" drugs merely on the basis of anticholinergic potency. Thus, either outcome would add significantly to our knowledge of atypical antipsychotic drugs, and aid development of new drugs with significantly lessened side effect liability. The health relatednes of such work is clear and straightforward - the development of better drugs for treating mental illness.

这项研究的目的是为了深入了解大脑临床非典型抗精神病药物的作用机制氯氮平在抗精神分裂症药物中，几乎不会产生锥体外系副作用或迟发性运动障碍，通常是严重的神经系统副作用，其他抗精神病药物被认为是由抗精神病药物引起的黑质纹状体功能障碍多巴胺（DA）系统。大量的研究，实验室和其他地方，强烈表明，氯氮平，选择性地在中脑边缘作为功能性DA拮抗剂 DA系统，而实际上保留黑质纹状体系统。这氯氮平独特药理作用部位特异性解释简介在许多方面都很有吸引力，其中最重要的是事实上，目前用于筛选潜在药物的药理学方法新的抗精神病药物（目前不区分之间的mesolimbic和nigrostriatal特异性）可能是修饰以仅选择具有位点特异性的化合物中脑边缘轮廓为此，我们制定了一个颅内电刺激（ICSS）的适应性这是高度准确的区分氯氮平的范例从解剖学上更弥散的中边缘部位特异性经典精神抑制剂的DA拮抗作用。使用的范例这些研究，并用于目前的工作，是慢性抗精神病药诱导的功能性DA超敏反应 ICSS评估的中脑边缘和黑质纹状体DA基因座模型我们现在寻求资金来扩展我们以前的工作，解决以下问题-是氯氮平的中脑边缘功能性特异性是由于氯氮平的强大内在抗胆碱能效力？如果回答“是”，具有氯氮平样内源性的抗精神分裂症药物抗胆碱能的效力似乎是有保证的。如果“否”，氯氮平独特的非典型特征必然是其他神经药理学机制，可能包括对中脑边缘与黑质纹状体突触前的差异作用调节机制此外，如果“否”，ICSS的实用性筛选潜在的新型抗精神病药物的范例将是巨大的，因为它不会检测到“假阳性”药物仅仅基于抗胆碱能的效力。因此，结果将显着增加我们对非典型的了解抗精神病药物，并帮助开发新药，大大减少了副作用的责任。与健康有关的这种工作是明确和直接的-发展治疗精神疾病的更好药物。