Tracking effects of oxytocin crossing the blood brain barrier in vivo and in vitro
Date
2017
Authors
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Publisher
University of Delaware
Abstract
Oxytocin is widely used in clinical trials to treat diseases that manifest from central nervous system dysfunction. Peripheral administration of oxytocin- both subcutaneous and intranasal- have efficacious effects on symptoms of autism, schizophrenia, PTSD, and anxiety. The behavioral outcomes of oxytocin treatment are assumed to derive from central effects in the brain. However, how oxytocin crosses into brain through the blood brain barrier to alter central nervous system function is not well understood. In addition, little is known about the cellular mechanisms by which exogenous oxytocin might modulate behavioral outcomes. This dissertation examines the role of exogenous oxytocin in modulating brain activity and behavior. The first aim of this dissertation is to determine whether oxytocin crosses through the blood brain barrier. To that effect, varying doses of oxytocin are applied to the luminal side of an artificial blood brain. Oxytocin that crosses to the luminal side is assayed with an ELISA. The second aim of this dissertation is to determine how oxytocin administered intranasally or subcutaneously changes plasma oxytocin concentration and gene expression in brain. Rats are dosed with varying doses of oxytocin intranasally or subcutaneously. After 30 minutes, plasma is extracted and oxytocin concentration is measured using an ELISA. Egr-1 gene expression in brain regions associated with oxytocin production, oxytocin receptor activity and oxytocin-mediated behavioral outcomes is assayed using in situ hybridization. The results of these studies indicate that higher doses of oxytocin cross an artificial blood brain barrier in higher concentrations than lower doses. These findings are used to develop a dose-response curve of oxytocin penetration of the blood brain barrier, which is then used to predict how oxytocin may cross the blood brain barrier in vivo. These results also demonstrate that higher doses of both intranasal and subcutaneous oxytocin administration increase plasma oxytocin concentration significantly above vehicle controls. Using the model developed in the previous aim, high doses of subcutaneous oxytocin are expected to penetrate the blood brain barrier. However, compared to subcutaneous administration, high doses of intranasal oxytocin cannot penetrate the blood brain barrier, although they too increase plasma oxytocin significantly above home cage controls. In brain, both subcutaneous and intranasal oxytocin alter Egr-1 gene expression. High intranasal and subcutaneous doses increase gene expression in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala. A high subcutaneous dose also increases Egr-1 activity in the anterior division of the bed nucleus of the
stria terminalis. Together, these findings suggest that oxytocin passes through the blood brain barrier and modulates brain activity through an Egr-1 mediated mechanism. Behavioral effects reported in other studies may be modulated by the changes in central nervous system activity reported here. These findings have implications for the use of oxytocin in treating clinical disorders.
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Keywords
Biological sciences, Blood brain barrier, Egr-1, Intranasal, Oxytocin, Subcutaneous