Antipsychotics, hypoglycemia, glutamate and cognition

描述(申请人提供)：严重的低血糖发作在糖尿病患者中是常见的。然而，低血糖和抗精神病药物之间的一个重要相互作用在很大程度上被忽视了。患糖尿病的风险在精神分裂症患者中增加一倍，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导致认知障碍。典型的抗精神病药物如氟哌啶醇通过拮抗多巴胺D2和5羟色胺5HT1a受体的作用来升高细胞外谷氨酸，而5羟色胺5HT2a受体拮抗剂则抑制谷氨酸的释放。谷氨酸通过对离子受体通道的影响以及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性毒性。氟哌啶醇可通过升高细胞外谷氨酸，加重胰岛素诱导的低血糖时的认知功能障碍。相比之下，替代的非典型抗精神病药物，包括奎硫平和阿立哌唑，具有限制细胞外谷氨酸的药理学特性，在这种情况下可能具有神经保护作用。该应用的目的是确定氟哌啶醇、奎硫平和阿立哌唑对胰岛素诱导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，奎硫平和阿立哌唑的D2拮抗作用更有限，5HT2A亲和力增加，5HT1A部分激动剂减少细胞外谷氨酸，改善认知结果。我们将在特定的目标1中通过测量在胰岛素诱导的低血糖期间使用氟哌啶醇、奎硫平、阿立哌唑或赋形剂治疗的大鼠的细胞外谷氨酸来检验这一假设。我们希望观察到与氟哌啶醇相比，奎硫平和阿立哌唑治疗的细胞外谷氨酸减少，这表明了一种在神经化学上相关但未被认可的方法，将奎硫平和阿立哌唑与典型的精神病药物区分开来。在特定的目标2中，我们将测量在胰岛素诱导的低血糖期间使用氟哌啶醇、奎硫平、阿立哌唑或赋形剂治疗的大鼠的认知结果。我们希望确定使用奎硫平和阿立哌唑治疗的大鼠的认知能力与氟哌啶醇相比有所改善，证明了替代治疗产生的功能改善。拟议的研究是创新的，因为虽然人们普遍认识到包含氟哌啶醇和胰岛素诱导的低血糖之间相互作用的风险的每个步骤，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3500万服用抗精神病药物的糖尿病患者的安全性。 公共健康相关性：我们建议确定抗精神病药物氟哌啶醇、奎硫平和阿立哌唑对胰岛素诱导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，奎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的措施，将奎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.