CLOZAPIN--CHOLINERGIC BASIS OF MESOLIMBIC SPECIFICITY

这项研究的目的是深入了解大脑 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独一无二的氯氮平 几乎不会产生锥体外系副作用或迟缓 运动障碍，通常是严重的神经副作用， 其他抗精神病药物被认为是由 抗精神病药物所致黑质纹状体功能障碍 多巴胺(DA)系统。大量的研究，都来自于这个 实验室和其他地方，强烈建议氯氮平 选择性地作为功能性DA拮抗剂存在于中脑边缘 DA系统，而实际上省去了黑质纹状体系统。这 氯氮平独特药理作用的部位特异性解释 个人资料在许多方面都很有吸引力，其中最重要的是 事实是，目前筛选潜力的药理学方法 新的抗精神病药物(目前不区分 中边缘和黑质纹状体之间的特异性)可能是 被修改为只选择具有特定位点的化合物 中边缘剖面。为此，我们开发了一种 颅内电刺激(ICSS)的适应性 区分氯氮平的高度准确的范例 更具解剖弥漫性的中脑边缘部位特异性 经典抗精神病药的DA拮抗作用。所使用的范例 这些研究，并将用于目前的工作，是 慢性抗精神病药物诱导的功能性多巴胺超敏反应 ICSS对中边缘和黑质纹状体DA基因座的评估 模特。我们现在寻求资金，以延长我们以前的工作 回答以下问题-氯氮平的中脑边缘 功能特异性是氯氮平强大的结果 内在的抗胆碱能药效？如果是，则表示新的 具有氯氮平类内源性的抗精神分裂症药物 抗胆碱能药效似乎是有根据的。如果“否”， 氯氮平独特的非典型特征必须从逻辑上推导出 其他神经药理机制，可能包括 中脑边缘突触与黑质纹状体前突触的区别作用 调节机制。此外，如果“否”，ICSS的效用 筛选潜在抗精神病新药的范例将是 是巨大的，因为它不会检测到“假阳性”的药物 仅仅基于抗胆碱能的效力。因此，无论是 结果将大大增加我们对非典型肺炎的认识 抗精神病药物，并帮助开发新药 显著减少了副作用责任。与健康有关的问题 这类工作的发展是明确和直接的-- 治疗精神疾病的更好的药物。

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.