Fluoxetine Maintains a State of Heightened Responsiveness to Motor Training Early After Stroke in a Mouse Model

• Published in: Stroke (1970) Vol. 46; no. 10; pp. 2951 - 2960
• Main Authors: Ng, Kwan L, Gibson, Ellen M, Hubbard, Robert, Yang, Juemin, Caffo, Brian, O’Brien, Richard J, Krakauer, John W, Zeiler, Steven R
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01-10-2015
• Subjects: Animals; Behavior, Animal - drug effects; Disease Models, Animal; Fluoxetine - pharmacology; Male; Mice; Motor Activity - drug effects; Motor Cortex - drug effects; Motor Cortex - pathology; Motor Cortex - physiopathology; Motor Skills - drug effects; Movement - drug effects; Neurological Rehabilitation; Neuronal Plasticity - drug effects; Recovery of Function - drug effects; Selective Serotonin Reuptake Inhibitors - pharmacology; Stroke - pathology; Stroke - physiopathology; Stroke Rehabilitation; Time-to-Treatment; neuronal plasticity; fluoxetine; motor cortex; recovery; stroke; upper extremity
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.115.010471

BACKGROUND AND PURPOSE—Data from both humans and animal models suggest that most recovery from motor impairment after stroke occurs in a sensitive period that lasts only weeks and is mediated, in part, by an increased responsiveness to training. Here, we used a mouse model of focal cortical stroke to test 2 hypotheses. First, we investigated whether responsiveness to training decreases over time after stroke. Second, we tested whether fluoxetine, which can influence synaptic plasticity and stroke recovery, can prolong the period over which large training-related gains can be elicited after stroke.
METHODS—Mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent stroke induction in the caudal forelimb area. The mice were then retrained after a 1- or 7-day delay with and without fluoxetine.
RESULTS—Recovery of prehension after a caudal forelimb area stroke was complete if training was initiated 1 day after stroke but incomplete if it was delayed by 7 days. In contrast, if fluoxetine was administered at 24 hours after stroke, then complete recovery of prehension was observed even with the 7-day training delay. Fluoxetine seemed to mediate its beneficial effect by reducing inhibitory interneuron expression in intact premotor cortex rather than through effects on infarct volume or cell death.
CONCLUSIONS—There is a gradient of diminishing responsiveness to motor training over the first week after stroke. Fluoxetine can overcome this gradient and maintain maximal levels of responsiveness to training even 7 days after stroke.