Antipsychotics, hypoglycemia, glutamate and cognition

抗精神病药、低血糖、谷氨酸和认知

基本信息

批准号：
7530688
负责人：
NEIL MARK RICHTAND
金额：
$ 21.06万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-20 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7530688
关键词：
Adverse effects Affinity Agonist Antipsychotic Agents Awareness Clinical Cognition Cognitive Communities Data Diabetes Mellitus Dopamine Dopamine D2 Receptor Elevation Excitatory Amino Acid Antagonists Glutamates Goals Haloperidol Hypoglycemia Impaired cognition Individual Insulin Knowledge Lead Measurable Measures Mediating Medical Methods Modeling Outcome Oxidative Stress Pathway Pathway interactions Patients Pharmaceutical Preparations Property Public Health Rattus Relative (related person)Research Design Risk Safety Schizophrenia Serotonin Testing Toxic effect aripiprazole atypical antipsychotic base clinically relevant diabetes risk diabetic expectation extracellular functional improvement improved innovation interest neurochemistry neuroprotection neurotoxic neurotoxicity pre-clinical preclinical study quetiapine receptor type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): Severe hypoglycemic episodes are a common occurrence among diabetic patients. An important interaction between hypoglycemia and antipsychotic medications, however, has gone largely unnoticed. The risk for diabetes is doubled in schizophrenia, and hypoglycemic episodes are a common side effect of treatment for both type 1 and type 2 diabetes. Preclinical studies demonstrate cognitive impairment mediated by elevated glutamate following insulin-induced hypoglycemia. Typical antipsychotic medications such as haloperidol elevate extracellular glutamate through antagonist effects on dopamine D2 and serotonin 5HT1A receptors, while serotonin 5HT2A receptor antagonists inhibit glutamate release. Glutamate is excitotoxic through effects on ionotropic receptor channels and synergistic effects with other neurotoxic pathways activated by hypoglycemia. Haloperidol could worsen the cognitive dysfunction of insulin-induced hypoglycemia by elevating extracellular glutamate. In contrast, alternative atypical antipsychotic medications including quetiapine and aripiprazole have pharmacological properties limiting extracellular glutamate and may be neuroprotective in this setting. The objective of this application is to determine the relative effects of haloperidol, quetiapine and aripiprazole on extracellular glutamate and cognitive outcome following insulin-induced hypoglycemia. We hypothesize quetiapine and aripiprazole's more limited D2 antagonism, increased 5HT2A affinity, and 5HT1A partial agonism decrease extracellular glutamate and improve cognitive outcome compared to haloperidol. We will test this hypothesis in Specific Aim 1 by measuring extracellular glutamate in rats treated with haloperidol, quetiapine, aripiprazole or vehicle during insulin-induced hypoglycemia. We expect to observe decreased extracellular glutamate with quetiapine and aripiprazole treatment compared to haloperidol, demonstrating a neurochemically relevant but unappreciated measure distinguishing quetiapine and aripiprazole from typical psychotics. In Specific Aim 2, we will measure cognitive outcome in rat treated with haloperidol, quetiapine, aripiprazole or vehicle during insulin-induced hypoglycemia. We expect to identify improved cognition in rats treated with quetiapine and aripiprazole compared to haloperidol, demonstrating a functional improvement resulting from alternative treatment. The proposed studies are innovative in that while there is widespread recognition of each individual step comprising the risk of interaction between haloperidol and insulin-induced hypoglycemia, awareness of the resulting medical significance is limited. The clinical implication of this study is that it could immediately lead to improved safety for 35 million diabetic patients worldwide taking antipsychotic medications. PUBLI HEALTH RELEVANCE: We propose to determine the effect of the antipsychotic medications haloperidol, quetiapine, and aripiprazole on extracellular glutamate, and cognitive outcome, following insulin-induced hypoglycemia. We expect to observe decreased extracellular glutamate, and improved cognitive outcome, in rats treated with quetiapine and aripiprazole compared to haloperidol. These outcomes are important because they will demonstrate a neurochemically relevant measure distinguishing quetiapine and aripiprazole from typical antipsychotic medications which may lead to improved safety for diabetic patients taking antipsychotic medications.

描述（由申请人提供）：严重低血糖发作在糖尿病患者中很常见。然而，低血糖和抗精神病药物之间的重要相互作用却基本上没有被注意到。精神分裂症患者患糖尿病的风险加倍，低血糖发作是 1 型和 2 型糖尿病治疗的常见副作用。临床前研究表明，胰岛素引起的低血糖后谷氨酸升高会介导认知障碍。典型的抗精神病药物（例如氟哌啶醇）通过对多巴胺 D2 和血清素 5HT1A 受体的拮抗作用来升高细胞外谷氨酸，而血清素 5HT2A 受体拮抗剂则抑制谷氨酸释放。谷氨酸通过影响离子型受体通道以及与低血糖激活的其他神经毒性途径的协同作用而具有兴奋毒性。氟哌啶醇可以通过升高细胞外谷氨酸来恶化胰岛素引起的低血糖的认知功能障碍。相比之下，包括喹硫平和阿立哌唑在内的替代非典型抗精神病药物具有限制细胞外谷氨酸的药理学特性，并且在这种情况下可能具有神经保护作用。本申请的目的是确定氟哌啶醇、喹硫平和阿立哌唑对胰岛素引起的低血糖后细胞外谷氨酸和认知结果的相对影响。我们假设与氟哌啶醇相比，喹硫平和阿立哌唑的 D2 拮抗作用更有限，5HT2A 亲和力增加，并且 5HT1A 部分激动可减少细胞外谷氨酸并改善认知结果。我们将在具体目标 1 中通过测量在胰岛素诱导的低血糖期间接受氟哌啶醇、喹硫平、阿立哌唑或媒介物治疗的大鼠的细胞外谷氨酸来检验这一假设。我们期望观察到与氟哌啶醇相比，喹硫平和阿立哌唑治疗的细胞外谷氨酸减少，这证明了一种神经化学相关但未被重视的措施，将喹硫平和阿立哌唑与典型精神病患者区分开来。在具体目标 2 中，我们将测量在胰岛素诱导的低血糖期间接受氟哌啶醇、喹硫平、阿立哌唑或媒介物治疗的大鼠的认知结果。我们期望确定与氟哌啶醇相比，接受喹硫平和阿立哌唑治疗的大鼠认知能力有所改善，证明替代治疗带来的功能改善。拟议的研究具有创新性，因为虽然人们广泛认识到每个单独步骤都存在氟哌啶醇和胰岛素引起的低血糖之间相互作用的风险，但对由此产生的医学意义的认识有限。这项研究的临床意义在于，它可以立即提高全球 3500 万糖尿病患者服用抗精神病药物的安全性。公共健康相关性：我们建议确定抗精神病药物氟哌啶醇、喹硫平和阿立哌唑对胰岛素引起的低血糖后细胞外谷氨酸和认知结果的影响。我们期望观察到，与氟哌啶醇相比，用喹硫平和阿立哌唑治疗的大鼠细胞外谷氨酸减少，认知结果改善。这些结果很重要，因为它们将证明一种神经化学相关措施将喹硫平和阿立哌唑与典型的抗精神病药物区分开来，这可能会提高服用抗精神病药物的糖尿病患者的安全性。