Defense Date

2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Anatomy & Neurobiology

First Advisor

Robert J. Hamm

Second Advisor

Linda L. Phillips

Abstract

Catecholaminergic neurotransmission is regionally altered following injury, and drugs aimed at these systems offer promising avenues for post-TBI pharmacotherapies. Atomoxetine is a selective norepinephrine transporter (NET) inhibitor currently indicated for treatment of attention-deficit hyperactivity disorder (ADHD). The studies in this dissertation were designed to test the efficacy of atomoxetine for treating cognitive deficits following experimental TBI and the potential mechanism for any beneficial effect. The first part of the study focused on behavioral recovery following atomoxetine treatment. Several important questions of dose, therapeutic window, and duration of treatment were addressed in these studies. Sprague-Dawley rats were subjected to lateral fluid-percussion injury (L-FPI) of moderate severity (2.08 atm +/- .05). Four experiments were performed. In the first study, atomoxetine (.3 mg/kg, 1mg/kg, 3 mg/kg, or 9 mg/kg) or vehicle was administered daily on post injury days (PID) 1-15. Cognitive assessment was performed using the Morris water maze on PID 11-15. L-FPI resulted in significant cognitive impairment when compared to Sham-Injury. Treatment with lower doses of atomoxetine (.3mg/kg, 1mg/kg, and 3mg/kg) significantly attenuated the cognitive deficits in injured animals. Treatment with the higher dosage (9mg/kg) of atomoxetine resulted in animals that were not significantly different than injured-vehicle treated animals. The optimal response was achieved using 1 mg/kg atomoxetine. In the second study, treatment with atomoxetine (1mg/kg) or vehicle was delayed for 11 days post-injury. Rats were administered atomoxetine daily for 15 days and cognitive assessment was performed on PID 25-29. In this study, treatment with atomoxetine (1 mg/kg) did not result in improved cognitive performance. In the next study atomoxetine was given daily on PID 1-7 and then treatment was terminated. The animals were tested in the MWM on PID 11-15. We found that atomoxetine treatment for 7 days post-injury provides an enhancement of cognitive deficits that is not significantly different from sham animals. We then investigated whether a single treatment of atomoxetine 24 h after brain injury could influence behavioral outcome on days 11-15. From this study, we found a single dose of atomoxetine is not as effective as chronic treatment. Finally, we investigated changes in the protein expression of brain-derived neurotrophic factor, growth-associated protein-43, and synaptophysin on day 7 PID to investigate what effect atomoxetine may have on brain plasticity and regeneration. We found that atomoxetine can enhance both GAP-43 and BDNF, but not synaptophysin at this time point. In conclusion, this is the first study to show that low doses of atomoxetine initiated early after experimental traumatic brain injury results in improved cognition. Furthermore, we show that enhancement of catecholamines via atomoxetine treatment during periods of postinjury-induced plasticity can provide long-term functional and structural benefits.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-11-2008

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