ANTIPSYCHOTIC DRUG EFFECTS--TSTS OF NE VS DA MECHANISM

抗精神病药物作用--NE与DA机制的比较

基本信息

批准号：
3381720
负责人：
BRUCE N COHEN
金额：
$ 12.82万
依托单位：
MCLEAN HOSPITAL
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：
1988-04-01 至 1992-03-31
项目状态：
已结题

项目摘要

The dopamine antagonist properties of antipsychotic drugs have been thoroughly studied in vitro and in vivo, and most, but not all, are potent antagonists of dopamine D-2 receptors. Antipsychotic drugs are also potent antagonists at alpha-1 noradrenergic receptors. However, the relative alpha-1 noradrenergic antagonist activity of antipsychotic drugs has rarely been determined in vivo, especially during extended treatment. Such treatment provides a better model of clinical drug effects than the more frequently determined potencies of drugs in vitro, such as in test tube assays of competition for binding sites. To test the hypothesis that effective antipsychotic drugs are effective alpha- 1 noradrenergic antagonists at clinically relevant doses in vivo, rats will receive repeated antipsychotic drug treatment. Following treatment, the affinity and density of binding at dopamine D2 and alpha-1 noradrenergic receptor sites will be determined in striatum and brain exclusive of striatum, respectively. Effective antagonism should lead to an increase in density of the relevant receptors. Preliminary in vivo experiments suggest that all clinically proved antipsychotic drugs are effective antagonists at alpha-1 noradrenergic receptors, but not all are potent at dopamine D-2 receptors. The range of drugs tested will now be enlarged. Various typical and "atypical" neuroleptics, as well as drugs representing the available chemical classes of antipsychotic agents will be studied. For comparison, agents which are not clinically effective antipsychotic drugs, in particular, antidepressant drugs, which are moderately potent alpha-1 an dopamine D-2 antagonists in vitro, will be studied. As effective alpha-1 noradrenergic antagonism may produce adrenergic supersensitivity, in addition to receptor upregulation, alterations in alpha-1 noradrenergic-mediated behavior will be monitored in test animals following ICV injections of the alpha-1 agonist phenylephrine. (Supersensitivity of dopaminergic systems after treatment with antipsychotic drugs has already been well studied.) These studies will help to clarify the relative roles of dopamine D-2 and alpha-1 noradrenergic antagonism in producing the therapeutic effects of antipsychotic drugs. The "dopamine hypothesis" of antipsychotic drug actions has not led to breakthroughs in the understanding of psychosis or to more effective or safer treatments. Increased knowledge of the mechanisms of action of the antipsychotic drugs should aid in developing better drugs with a more favorable ratio of efficacy to unnecessary side effects. In addition, such knowledge may provide clues regarding the pathophysiology of the idiopathic psychoses.

抗精神病药的多巴胺拮抗剂具有在体外和体内进行了彻底研究，大多数但不是全部，是多巴胺D-2受体的有效拮抗剂。抗精神病药药物在alpha-1去甲肾上腺素能中也是有效的拮抗剂受体。但是，相对α-1甲肾上腺素能抗精神病药的拮抗剂活性很少确定体内，尤其是在扩展治疗期间。这样的治疗提供了比临床药物影响更好的模型体外药物的效力更频繁，这样就像在测试管中的竞争对绑定位点的竞争。测试假设有效的抗精神病药是有效的α- 1在体内临床相关剂量的去甲肾上腺素能拮抗剂，大鼠将重复接受抗精神病药物治疗。处理后，结合的亲和力和密度多巴胺D2和Alpha-1去甲肾上腺素能受体位点将是在纹状体和大脑中确定，不包括纹状体，分别。有效的对抗应导致增加相关受体的密度。体内初步实验表明所有临床证明的抗精神病药是α-1甲肾上腺素能受体的有效拮抗剂，但在多巴胺D-2受体下并非所有人都有效力。毒品范围现在测试将扩大。各种典型和“非典型” 神经疗法以及代表可用化学物质的药物将研究一类抗精神病药。为了进行比较，不是临床上有效抗精神病药的药物，特别有效的抗抑郁药将研究体外的α-1和多巴胺D-2拮抗剂。作为有效的α-1去甲肾上腺素能拮抗可能会产生除了受体上调外，肾上腺素能超敏反应 α-1去甲肾上腺素介导的行为的改变将是在ICV注射α-1后，在测试动物中监测激动剂苯肾上腺素。（多巴胺能系统的超敏用抗精神病药治疗后已经很好研究。）这些研究将有助于阐明多巴胺D-2和Alpha-1去甲肾上腺素能拮抗作用抗精神病药的治疗作用。 “多巴胺假设“抗精神病药作用尚未导致在理解精神病或更多方面的突破有效或更安全的治疗方法。越来越了解抗精神病药的作用机制应有助于开发更好的药物，其功效比率更高不必要的副作用。此外，这种知识可能提供有关特发性病理生理学的线索精神病。