Post-injury atomoxetine treatment improves cognition following experimental traumatic brain injury

J Neurotrauma. 2008 Mar;25(3):248-56. doi: 10.1089/neu.2007.0389.

Abstract

Catecholaminergic neurotransmission is regionally altered following injury, and drugs aimed at these systems offer promising avenues for post-traumatic brain injury (TBI) pharmacotherapies. Atomoxetine is a selective norepinephrine transporter (NET) inhibitor currently indicated for treatment of attention-deficit hyperactivity disorder (ADHD). The current study was designed to test the efficacy of atomoxetine in treating cognitive deficits following experimental TBI in animals and to determine an optimal dose and therapeutic window for drug treatment. Sprague-Dawley rats were subjected to lateral fluid-percussion injury (L-FPI) of moderate severity (2.08 atm +/- 0.05). Two experiments were performed. In the first study, atomoxetine (0.3, 1, 3, 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 (0.3, 1, and 3 mg/kg) significantly attenuated the cognitive deficits in injured animals. Treatment with the higher dosage (9 mg/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 (1 mg/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 conclusion, this is the first study to show low-dose atomoxetine initiated early after experimental TBI results in improved cognition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology
  • Adrenergic Uptake Inhibitors / therapeutic use
  • Animals
  • Atomoxetine Hydrochloride
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / physiopathology
  • Brain Injuries / complications*
  • Brain Injuries / drug therapy*
  • Brain Injuries / physiopathology
  • Catecholamines / metabolism
  • Cognition / drug effects
  • Cognition / physiology
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / etiology*
  • Cognition Disorders / physiopathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism
  • Propylamines / pharmacology*
  • Propylamines / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function / drug effects
  • Recovery of Function / physiology
  • Time Factors
  • Treatment Outcome

Substances

  • Adrenergic Uptake Inhibitors
  • Catecholamines
  • Norepinephrine Plasma Membrane Transport Proteins
  • Propylamines
  • Atomoxetine Hydrochloride