Modeling Antipsychotic-Induced Weight Gain in Rats

描述(由申请人提供)：本次修订的试探性/发展性拨款申请通过NIMH R21机制(PA-00-073)寻求资金，以进行探索性实验，以确定长期给药，通过持续输注抗精神病药物，以达到(人类)持续的治疗性血浆浓度是否会：(A)导致体重增加(主要目的)，和/或(B)修改下丘脑食欲控制回路中暗示食欲刺激的神经肽神经元(次要目的)。抗精神病药物会导致精神分裂症患者体重显著增加，但到目前为止，几乎所有的病例都是如此，而不是在大鼠身上。这种令人惊讶的物种二分法可能是由于长期(每天单次注射)给老鼠注射抗精神病药物的方式，以及老鼠的代谢率比人类更快，以至于老鼠每天只接触几个小时的治疗性血浆药物水平。在这个项目中，成年雄性和雌性大鼠将被植入Osmette小型泵，以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)28天。将监测食物摄入量、体重以及血液和脑部药物水平。将调整药物剂量，将血药浓度设定在临床有效范围内，以优化观察体重增加的机会。然后，我们将利用原位信使核糖核酸分析，探索下丘脑食欲控制回路(弓状神经肽-Y和阿片黑素原/α-MSH、室旁促肾上腺皮质激素释放激素和外侧下丘脑增食欲素)中神经肽神经元活性的变化。在大鼠身上成功识别出导致抗精神病药物导致体重增加的实验范式，将使其能够应用于研究导致这种不受欢迎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，将体重增加降至最低，同时保持抗精神病药物的疗效。

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.