Antipsychotics, hypoglycemia, glutamate and cognition

描述（申请人提供）：严重的低血糖发作是糖尿病患者的常见病。然而，降糖和抗精神病药物之间的重要相互作用在很大程度上被忽视了。精神分裂症患者患糖尿病的风险增加了一倍，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，胰岛素诱导的低血糖后，谷氨酸升高介导认知障碍。典型的抗精神病药物如氟哌啶醇通过对多巴胺D2和5 -羟色胺5HT1A受体的拮抗剂作用提高细胞外谷氨酸，而5 -羟色胺5HT2A受体拮抗剂抑制谷氨酸释放。谷氨酸通过对嗜离子受体通道的作用和与低血糖激活的其他神经毒性通路的协同作用而具有兴奋毒性。氟哌啶醇可通过提高细胞外谷氨酸而加重胰岛素性低血糖的认知功能障碍。相反，包括喹硫平和阿立哌唑在内的其他非典型抗精神病药物具有限制细胞外谷氨酸的药理特性，在这种情况下可能具有神经保护作用。本应用的目的是确定氟哌啶醇、喹硫平和阿立哌唑对胰岛素性低血糖后细胞外谷氨酸和认知结局的相对影响。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，5HT1A部分激动作用降低细胞外谷氨酸并改善认知结果。我们将在特异性目标1中通过测量大鼠在胰岛素诱导的低血糖期间接受氟哌啶醇、喹硫平、阿立哌唑或对照物治疗的细胞外谷氨酸来验证这一假设。我们期望观察到与氟哌啶醇相比，喹硫平和阿立哌唑治疗降低了细胞外谷氨酸，这表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的精神病区分开来。在特异性目标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、阿立哌唑或载药治疗的大鼠的认知结果。我们期望确定与氟哌啶醇相比，用喹硫平和阿立哌唑治疗的大鼠的认知能力得到改善，证明替代治疗导致的功能改善。拟议的研究具有创新性，因为虽然人们普遍认识到每一个步骤都包含氟哌啶醇与胰岛素诱导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是，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。

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.