Modeling Antipsychotic-Induced Weight Gain in Rats

抗精神病药引起的大鼠体重增加建模

• 批准号: 6838732
• 负责人: JOHN D FERNSTROM
• 金额: $ 14.11万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-24 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6838732
• 关键词: antipsychotic agents; appetite; appetite regulatory center; behavioral /social science research tag; body weight; dosage; drug adverse effect; high performance liquid chromatography; hypothalamus; in situ hybridization; laboratory rat; microscopy; neurons; neuropeptides; nutrient intake activity; psychopharmacology; weight gain

DESCRIPTION (provided by applicant): This revised Exploratory/Developmental grant application seeks funding through an NIMH R21mechanism (PA- 00-073) to conduct exploratory experiments to determine if the chronic delivery to rat, of antipsychotic drugs by constant infusion, to achieve sustained, therapeutic plasma concentrations (for humans) will (a) cause body weight gain (primary aim), and/or (b) modify neuropeptide neurons in hypothalamic appetite control circuitry suggestive of appetite stimulation (secondary aim). Antipsychotic drugs cause significant weight gain in schizophrenic humans, but in almost all cases examined to date, not in rats. This surprising species dichotomy may be due to the manner used to deliver antipsychotics to rats, chronically (single, daily injections) and the more rapid metabolic rate in rats than in humans, such that rats are exposed only a few hours each day to therapeutic plasma drug levels. In this project, adult male and female rats will be implanted with Osmette minipumps to deliver a constant infusion of each of several antipsychotic drugs (haloperidol, clozapine, olanzapine, risperidone, sulpiride, ziprasidone) for 28 days. Food intake, body weight, and blood and brain drug levels will be monitored. Drug dose will be adjusted to set plasma concentrations in the clinically effective range to optimize the chance of observing weight gain. This paradigm will then be used to explore for changes, using in situ mRNA analysis, in the activity of neuropeptide neurons embedded in hypothalamic appetite control circuitry (arcuate neuropeptide-Y and proopiomelanocortin/alphaMSH, paraventricular corticotropin releasing hormone, and lateral hypothalamic orexin). The successful identification of an experimental paradigm in rats that cause, antipsychotics to induce weight gain would allow its application to the study of the underlying mechanisms causing this unwanted side-effect, and could then be applied to the development of adjunct or new treatments that would minimize weight gain, while maintaining antipsychotic efficacy.

描述（申请人提供）：此修订的探索/发展赠款申请通过NIMH R21机制寻求资金（PA- 00-073）进行探索性实验，以确定通过恒定输注向大鼠长期递送抗精神病药物是否达到持续的治疗血浆浓度（对于人）将（a）引起体重增加（主要目的），和/或（B）修饰暗示食欲刺激的下丘脑食欲控制回路中的神经肽神经元（次要目的）。抗精神病药物导致精神分裂症患者体重显著增加，但在迄今为止研究的几乎所有病例中，大鼠没有。这种令人惊讶的物种二分法可能是由于用于长期向大鼠递送抗精神病药物的方式（单次，每日注射）以及大鼠中比人类更快的代谢速率，使得大鼠每天仅暴露于治疗性血浆药物水平几个小时。在本项目中，成年雄性和雌性大鼠将植入Osmette微型泵，持续输注几种抗精神病药物（氟哌啶醇、氯氮平、奥氮平、利培酮、舒必利、齐拉西酮），持续28天。将监测摄食量、体重、血液和大脑药物水平。将调整药物剂量，以将血浆浓度设定在临床有效范围内，从而优化观察到体重增加的机会。然后，使用原位mRNA分析，该范例将用于探索嵌入下丘脑食欲控制回路中的神经肽神经元（弓状神经肽-Y和阿黑皮素原/α MSH、室旁促肾上腺皮质激素释放激素和外侧下丘脑食欲素）的活性的变化。在大鼠中成功识别导致抗精神病药物诱导体重增加的实验范例将允许其应用于研究导致这种不希望的副作用的潜在机制，然后可以应用于开发辅助或新的治疗方法，以最大限度地减少体重增加，同时保持抗精神病药物的疗效。