Acute Metabolic Effects of Olanzapine Depend on Dose and Injection Site.
Acute Metabolic Effects of Olanzapine Depend on Dose and Injection Site.
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DOI：
10.1177/1559325815618915
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Lynch CJ
中科院分区：
文献类型：
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作者：
Klingerman CM;Stipanovic ME;Hajnal A;Lynch CJ
非典型抗精神病药物（AAPs），如奥氮平（OLZ），与代谢副作用相关，包括高血糖。虽然已经提出了AAPs对血糖急性影响的中枢作用机制，但关于aap的外周作用和中枢作用的证据一直是混合的，并且尚未探讨OLZ对呼吸交换比（RER）的影响。在这里，我们验证了一个假设，即一些血糖反应的不一致可能是不同剂量和注射中心部位的结果。我们还比较了中枢和外周给药OLZ对未镇静大鼠内质网的影响。第三脑室输注0.3 mg/kg的OLZ可在30分钟内引起高血糖，需要更高剂量（1.8 mg/kg）才能在侧脑室引起类似的反应。相比之下，当给药时，3 mg/kg的OLZ需要在30分钟内提高血糖，10 mg/kg的OLZ导致高血糖持续至少60分钟。第三脑室注射OLZ在75分钟后显著降低RER，而灌胃OLZ在30分钟后使RER下降更快。由于OLZ输注到第三脑室时血糖变化最敏感，但当外周给药时观察到对内质网的影响更迅速有效，这些结果提高了涉及下丘脑和外周机制的双重作用机制的可能性。文献中关于中央给药的一些差异似乎是由注射部位和剂量引起的。
Atypical antipsychotics (AAPs), such as olanzapine (OLZ), are associated with metabolic side effects, including hyperglycemia. Although a central mechanism of action for the acute effects on glycemia has been suggested, evidence for peripheral versus central effects of AAPs has been mixed and has not been explored for an effect of OLZ on the respiratory exchange ratio (RER). Here, we tested the hypothesis that some inconsistencies in the glycemic responses are likely a result of different doses and central sites of injection. We also compared the effects of central versus peripherally administered OLZ on the RER of unsedated rats. Third ventricle infusion of OLZ at 0.3 mg/kg caused hyperglycemia within 30 minutes, with a higher dose (1.8 mg/kg) needed to elicit a similar response in the lateral ventricles. In contrast, 3 mg/kg of OLZ was needed to raise blood glucose within 30 minutes when given intragastrically, and 10 mg/kg resulted in a prolonged hyperglycemia lasting at least 60 minutes. Third ventricle injection of OLZ significantly decreased RER after 75 minutes, whereas intragastric OLZ resulted in a faster drop in RER after 30 minutes. Since changes in glycemia were most sensitive when OLZ was infused into the third ventricle, but effects on RER were more rapidly and efficaciously observed when the drug was given peripherally, these results raise the likelihood of a dual mechanism of action involving hypothalamic and peripheral mechanisms. Some discrepancies in the literature arising from central administration appear to result from the injection site and dose.