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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/3381720
• 关键词: alpha adrenergic receptor; alpha antiadrenergic agent; amitriptyline; antidepressants; antipsychotic agents; brain mapping; chemical binding; clozapine; computer data analysis; dopamine; dopamine receptor; dosage; drug administration rate /duration; drug administration routes; drug adverse effect; drug interactions; fluphenazine; haloperidol; injection /infusion; laboratory rat; neuropharmacology; phenylephrine; psychomotor function; psychopharmacology; receptor sensitivity

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.

抗精神病药物的多巴胺拮抗剂特性 已经在体外和体内进行了彻底的研究，并且大多数（但不是全部） 是多巴胺 D-2 受体的有效拮抗剂。 抗精神病药 药物也是 α-1 去甲肾上腺素能的有效拮抗剂 受体。 然而，相对α-1去甲肾上腺素能 抗精神病药物的拮抗活性很少被研究 体内测定，特别是在长期治疗期间。 这样的 与治疗相比，治疗提供了更好的临床药物效应模型 更频繁地测定药物的体外效力，例如 如在试管分析中竞争结合位点。 测试 假设有效的抗精神病药物是有效的α- 1 体内临床相关剂量的去甲肾上腺素能拮抗剂， 大鼠将接受反复的抗精神病药物治疗。 处理后，结合亲和力和密度 多巴胺 D2 和 α-1 去甲肾上腺素能受体位点 在纹状体和不包括纹状体的大脑中确定， 分别。 有效的拮抗作用应该会导致 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物 是 α-1 去甲肾上腺素能受体的有效拮抗剂，但是 并非所有药物都对多巴胺 D-2 受体有效。 药品范围 测试现在将被放大。 各种典型与“非典型” 抗精神病药以及代表可用化学物质的药物 将研究抗精神病药物的类别。 为了比较， 不是临床上有效的抗精神病药物的药物， 特别是抗抑郁药物，其效力中等 α-1 是一种多巴胺 D-2 拮抗剂，将在体外进行研究。 作为 有效的 α-1 去甲肾上腺素能拮抗作用可能会产生 肾上腺素能超敏反应，除了受体上调外， α-1 去甲肾上腺素能介导的行为的改变将是 在 ICV 注射 alpha-1 后对测试动物进行监测 激动剂去氧肾上腺素。 （多巴胺能系统的超敏感性 经抗精神病药物治疗后已痊愈 研究。）这些研究将有助于阐明 多巴胺 D-2 和 α-1 去甲肾上腺素能拮抗作用 抗精神病药物的治疗作用。 “多巴胺 抗精神病药物作用的假设”并未导致 对精神病的理解取得突破或更多 有效或更安全的治疗。 增加了相关知识 抗精神病药物的作用机制应有助于 开发更好的药物，具有更有利的疗效比 不必要的副作用。 此外，此类知识可能 提供有关特发性病理生理学的线索 精神病。