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：
7677249
负责人：
NEIL MARK RICHTAND
金额：
$ 17.55万
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 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7677249
关键词：
Adverse effects Affinity Agonist Antipsychotic Agents Awareness Clinical Cognition Cognitive Communities Data Diabetes Mellitus Dopamine Dopamine D2 Receptor 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 Pharmaceutical Preparations Property Public Health Rattus Relative (related person)Research Design Risk Safety Schizophrenia Serotonin Testing Toxic effect alternative treatment aripiprazole atypical antipsychotic base clinically relevant diabetes risk diabetic patient 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）：严重的降血糖发作是糖尿病患者的常见发生。然而，低血糖和抗精神病药之间的重要相互作用在很大程度上没有引起人们的注意。精神分裂症中糖尿病的风险增加了一倍，降血糖发作是1型和2型糖尿病的治疗的常见副作用。临床前研究表明，在胰岛素诱导的低血糖后，谷氨酸升高介导的认知障碍。典型的抗精神病药（例如氟哌啶醇）通过对多巴胺D2和5-羟色胺5HT1A受体的拮抗剂作用升高细胞外谷氨酸，而5-羟色胺5HT2A受体拮抗剂抑制了谷氨酸释放。谷氨酸通过对离子受体通道的影响和与其他神经毒性途径相关的兴奋性毒性和协同作用。氟哌啶醇可以通过升高细胞外谷氨酸来恶化胰岛素诱导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性非典型抗精神病药具有限制细胞外谷氨酸的药理特性，并且在这种情况下可能具有神经保护性。该应用的目的是确定氟哌啶醇，喹硫平和阿立哌唑对胰岛素诱导的低血糖后对细胞外谷氨酸和认知结果的相对影响。我们假设喹硫平和阿立哌唑更有限的D2拮抗作用，增加了5HT2A亲和力，而5HT1A部分激动剂减少了细胞外谷氨酸，并改善了与氟哌啶醇相比的认知结果。我们将通过在胰岛素诱导的低血糖中用氟哌啶醇，喹硫平，阿立哌唑或媒介物治疗的大鼠中测量细胞外谷氨酸在特定目标1中检验这一假设。与氟哌啶醇相比，我们预计将观察到喹硫平和阿立哌二唑治疗的细胞外谷氨酸降低，这表明与典型心理学区分开了神经化学与神经化学相关但无关紧要的措施。在特定的目标2中，我们将在胰岛素诱导的低血糖期间用氟哌啶醇，喹硫平，阿立哌唑或媒介物治疗的大鼠的认知结果。我们希望与氟哌啶醇相比，在用喹硫平和阿立哌唑治疗的大鼠中确定认知的改善，这表明替代治疗导致了功能性改善。拟议的研究具有创新性，尽管对每个单个步骤都有广泛认识，包括氟哌啶醇和胰岛素诱导的低血糖之间的相互作用风险，但对所得医学意义的认识是有限的。这项研究的临床意义是，它可以立即导致全球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：我们建议在胰岛素诱导的低血糖症后，确定抗精神病药氟哌啶醇，喹硫平和阿拉哌唑对细胞外谷氨酸和认知结果的影响。与氟哌啶醇相比，我们预计在用喹硫平和阿立哌唑治疗的大鼠中观察到细胞外谷氨酸的减少，并改善了认知结果。这些结果很重要，因为它们将展示一项与典型的抗精神病药区分开的神经化学措施，从而区分喹硫平和阿拉唑和阿里哌唑替代药物，这可能会改善服用抗精神病药的糖尿病患者的安全性。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evidence for involvement of nitric oxide and GABA(B) receptors in MK-801- stimulated release of glutamate in rat prefrontal cortex.

DOI：
10.1016/j.neuropharm.2012.04.032
发表时间：
2012-09
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Roenker NL;Gudelsky GA;Ahlbrand R;Horn PS;Richtand NM
通讯作者：
Richtand NM

Fluoxetine and aripiprazole treatment following prenatal immune activation exert longstanding effects on rat locomotor response.

产前免疫激活后的氟西汀和阿立哌唑治疗对大鼠运动反应产生长期影响。

DOI：
10.1016/j.physbeh.2012.02.004
发表时间：
2012
期刊：
Physiology & behavior
影响因子：
2.9
作者：
Richtand,NeilM;Ahlbrand,Rebecca;Horn,Paul;Tambyraja,Rabindra;Grainger,Molly;Bronson,StefanieL;McNamara,RobertK
通讯作者：
McNamara,RobertK

Effect of paliperidone and risperidone on extracellular glutamate in the prefrontal cortex of rats exposed to prenatal immune activation or MK-801.

DOI：
10.1016/j.neulet.2011.06.011
发表时间：
2011-08-18
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Roenker NL;Gudelsky G;Ahlbrand R;Bronson SL;Kern JR;Waterman H;Richtand NM
通讯作者：
Richtand NM

Individual differences in maternal response to immune challenge predict offspring behavior: contribution of environmental factors.

DOI：
10.1016/j.bbr.2010.12.040
发表时间：
2011-06-20
期刊：
BEHAVIOURAL BRAIN RESEARCH
影响因子：
2.7
作者：
Bronson, Stefanie L.;Ahlbrand, Rebecca;Horn, Paul S.;Kern, Joseph R.;Richtand, Neil M.
通讯作者：
Richtand, Neil M.

Effects of prenatal immune activation and peri-adolescent stress on amphetamine-induced conditioned place preference in the rat.

DOI：
10.1007/s00213-012-2646-8
发表时间：
2012-07
期刊：
PSYCHOPHARMACOLOGY
影响因子：
3.4
作者：
Richtand, Neil M.;Ahlbrand, Rebecca;Horn, Paul S.;Chambers, Brad;Davis, Jon;Benoit, Stephen
通讯作者：
Benoit, Stephen