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Treatment with low-dose methamphetamine improves behavioral and cognitive function after severe traumatic brain injury

Rau, Thomas F. PhD; Kothiwal, Aakriti S. BS; Rova, Annela R. BA; Brooks, Diane M. BS; Poulsen, David J. PhD

Journal of Trauma and Acute Care Surgery: August 2012 - Volume 73 - Issue 2 - p S165–S172
doi: 10.1097/TA.0b013e318260896a

BACKGROUND Methamphetamine increases the release and blocks the reuptake of dopamine. The moderate activation of dopamine receptors may elicit neuroprotective effects. We have recently demonstrated that low doses of methamphetamine reduce neuronal loss after ischemic injury. On the basis of this finding, we hypothesized that methamphetamine could also prevent neuronal loss and improve functional behavior after severe traumatic brain injury (TBI).

METHODS The rat lateral fluid percussion injury model was used to generate severe TBI. Three hours after injury, animals were treated with saline or methamphetamine. Neurological severity scores and foot fault assessments were used to determine whether treatment enhanced recovery after injury. The potential for methamphetamine treatment to improve cognitive function was assessed using the Morris water maze. Forty-eight hours after injury, paraffin-embedded brain sections were TUNEL stained to measure apoptotic cell death. Sections were also stained with antibody to doublecortin to quantify immature neurons within the dentate gyrus.

RESULTS Treatment with low-dose methamphetamine significantly reduced both behavioral and cognitive dysfunction after severe TBI. Methamphetamine-treated animals scored significantly lower on neurological severity scores and had significantly less foot faults after TBI compared with saline-treated control rats. Furthermore, methamphetamine treatment restored learning and memory function to near normal ability after TBI. At 48 hours after injury, apoptotic cell death within the hippocampus was significantly reduced, and the presence of immature neurons was significantly increased in methamphetamine-treated rats compared with saline-treated controls.

CONCLUSION Treatment with low-dose methamphetamine after severe TBI elicits a robust neuroprotective response resulting in significant improvements in behavioral and cognitive functions.

From the Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula.

This study was presented at the Advanced Technology Applications for Combat Casualty Care Conference in Fort Lauderdale, Florida, August 15–18, 2011.

Address for reprints: David J. Poulsen, PhD, Department of Biomedical and Pharmaceutical Sciences, University of Montana, 32 Campus Dr, Missoula, MT 59812; email:

© 2012 Lippincott Williams & Wilkins, Inc.