Section on Neural Gene Expression, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA; Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
Section on Neural Gene Expression, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA; Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.
Pharmacol Res. 2019 Aug;146:104324. doi: 10.1016/j.phrs.2019.104324. Epub 2019 Jun 22.
Intranasal delivery of oxytocin (Oxt) has been identified as a potential therapeutic to target human conditions characterized by social deficits, yet the ability of this administrative route to deliver to the brain is unconfirmed. Oxt knockout (Oxt KO) and wildtype C57BL/6 J male mice received Oxt (12 μg total amount) either by nasal or intraperitoneal administration. Oxt concentrations were monitored for 2 h after administration in circulation via a jugular vein catheter and in the brain by two intracerebral microdialysis probes. Group sizes varied from 4 to 7 mice (n = 22 total). We document for the first time that Oxt applied to the nasal mucosa after nasal administration is delivered to the extracellular fluid in the brain. After nasal application, Oxt concentrations in circulation and in the extracellular fluid of the amygdala and, to an extent, the dorsal hippocampus, rose within the first 30 min and remained elevated for the subsequent hour. These findings were confirmed in an Oxt KO mouse line, establishing that the circulating and brain Oxt elevations derive from the administered dose. Interestingly, the pharmacokinetics of Oxt were slightly biased to the brain after nasal administration and to the periphery following intraperitoneal injection. No change in vasopressin levels was detected. These findings have stimulating implications for the interpretation of various behavioral and physiological effects described in animal and human studies after nasal administration of Oxt and provide the pharmacokinetics necessary to develop this drug delivery route for therapeutic purposes.
鼻腔内给予催产素（Oxt）已被确定为一种有潜力的治疗方法，可以针对具有社交缺陷的人类疾病，但这种给药途径向大脑输送的能力尚未得到证实。催产素敲除（Oxt KO）和野生型 C57BL/6J 雄性小鼠通过鼻腔或腹腔内给药接受催产素（总量 12μg）。给药后 2 小时，通过颈静脉导管监测循环中的催产素浓度，并通过两个脑室内微透析探针监测大脑中的催产素浓度。每组大小从 4 到 7 只小鼠不等（n=22 只总）。我们首次记录到，鼻腔给药后应用于鼻黏膜的催产素被递送到大脑的细胞外液中。鼻腔给药后，催产素在循环中的浓度以及在杏仁核和背侧海马体的细胞外液中的浓度在最初的 30 分钟内升高，并在随后的 1 小时内保持升高。在 Oxt KO 小鼠系中证实了这些发现，从而确立了循环和大脑中的催产素升高来自于给予的剂量。有趣的是，催产素的药代动力学在鼻腔给药后稍微偏向于大脑，在腹腔内注射后偏向于外周。未检测到血管加压素水平的变化。这些发现对于解释在动物和人类研究中描述的各种行为和生理效应具有刺激意义，这些发现为开发这种药物输送途径用于治疗目的提供了必要的药代动力学。
