A Localized, Quantitative Drug Delivery Tool for Neurotransmission Studies Public Deposited

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  • March 19, 2019
  • Herr, Natalie Rios
    • Affiliation: College of Arts and Sciences, Department of Chemistry
  • Iontophoresis is the movement of charged molecules in solution under applied current using pulled multibarrel glass capillaries drawn to a sharp tip. The technique is commonly used in neuroscience as a localized drug delivery tool to target select brain regions. A major limitation of the technique is its non-quantitative nature and inherent variability between probes. In this dissertation, iontophoretic delivery has been coupled to fast-scan cyclic voltammetry for real-time monitoring of ejections. The ejection of charged and neutral species has been characterized with carbon-fiber microelectrodes coupled to iontophoresis barrels to reveal the mechanisms underlying drug delivery: iontophoretic and electroosmotic forces. With the use of the neutral, electroactive molecule 2-(4-nitrophenoxy) ethanol (NPE), which is only transported by electroosmotic flow (EOF), electroosmosis (EO) was identified as the major contributor to observed variability from probe to probe. In addition, differences in mobility for charged compounds were positively correlated to differences in electrophoretic mobility as determined by capillary electrophoresis (CE). Thus, CE can be used to predict the rate of transport for compounds that cannot be electrochemically monitored. With this information, quantitative iontophoresis is possible for electrochemically inactive drugs by using a marker molecule. This approach was validated in vivo in a well-understood biological system. Carbon-fiber/iontophoresis probes were used to measure and modulate electrically evoked dopamine release in the striatum of anesthetized rats. Dopamine release in this brain region is highly regulated by autoreceptors and the dopamine transporter. Iontophoretic ejections of an autoreceptor antagonist and a dopamine transporter inhibitor demonstrate that this technique can be used to locally modulate presynaptic release. Additionally, the experiments demonstrate that use of an internal marker molecule do not interfere with the biological results. The final chapters of this dissertation focus on the use of quantitative iontophoresis in novel applications, such as presynaptic regulation of norepinephrine and dopaminergic signaling in awake animals performing behaviors related to drug addiction.
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  • In Copyright
  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry."
  • Wightman, R. Mark
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  • Chapel Hill, NC
  • Open access

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