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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（申请人提供）：严重的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一个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了认知障碍。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5 HT 1A受体的拮抗作用升高细胞外谷氨酸，而5-羟色胺5 HT 2A受体拮抗剂抑制谷氨酸释放。谷氨酸通过对离子型受体通道的作用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而加重胰岛素诱导低血糖的认知功能障碍。相反，替代的非典型抗精神病药物，包括奎替鲁和阿立哌唑，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。本申请的目的是确定氟哌啶醇、奎替鲁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相对影响。我们假设与氟哌啶醇相比，奎替鲁和阿立哌唑的D2拮抗作用更有限，5 HT 2A亲和力增加，5 HT 1A部分激动作用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、奎替鲁、阿立哌唑或溶剂处理的大鼠的细胞外谷氨酸来检验这一假设。与氟哌啶醇相比，我们预期奎替利和阿立哌唑治疗可观察到细胞外谷氨酸盐降低，这表明奎替利和阿立哌唑与典型精神病患者之间存在神经化学相关但未被认可的差异。在具体目标2中，我们将测量在胰岛素诱导的低血糖期间用氟哌啶醇、奎替鲁、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，奎替鲁和阿立哌唑治疗的大鼠的认知改善，证明替代治疗导致的功能改善。拟定研究具有创新性，因为虽然氟哌啶醇和胰岛素诱导的低血糖之间相互作用风险的每个单独步骤都得到了广泛认可，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，它可以立即改善全球3500万服用抗精神病药物的糖尿病患者的安全性。公共卫生相关性：我们建议确定抗精神病药物氟哌啶醇、奎替利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。我们预期，与氟哌啶醇相比，奎替鲁和阿立哌唑治疗的大鼠细胞外谷氨酸减少，认知结果改善。这些结果是重要的，因为它们将证明一种神经化学相关的措施，将奎替鲁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。

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

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

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

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.

Dopaminergic regulation of dopamine D3 and D3nf receptor mRNA expression.

DOI：
10.1002/syn.20770
发表时间：
2010-08
期刊：
SYNAPSE
影响因子：
2.3
作者：
Richtand, Neil M.;Liu, Yanghong;Ahlbrand, Rebecca;Sullivan, Juliana R.;Newman, Amy Hauck;McNamara, Robert K.
通讯作者：
McNamara, Robert K.