Motor recovery and axonal plasticity with short-term amphetamine after stroke.
OBJECTIVE
There is considerable debate regarding the efficacy of amphetamine to facilitate motor recovery after stroke or experimental brain injury. Different drug dosing and timing schedules and differing physical rehabilitation strategies may contribute to outcome variability. The present study was designed to ascertain (1) whether short-term amphetamine could induce long-term functional motor recovery in rats after an ischemic lesion modeling stroke in humans; (2) how different levels of physical rehabilitation interact with amphetamine to enhance forelimb-related functional outcome; and (3) whether motor improvement was associated with axonal sprouting from intact corticoefferent pathways originating in the contralesional forelimb motor cortex.


METHODS
After permanent middle cerebral artery occlusion, rats received vehicle or amphetamine during the first postoperative week (2 mg/kg, subcutaneously on Postoperative Days 2, 5, and 8). In both treatment groups, separate cohorts of rats were exposed to different levels of "physical rehabilitation" represented by a control environment, enriched environment, or enriched environment with additional sessions of focused activity. Skilled forelimb performance was assessed using the forelimb reaching task and ladder rung walk test. Anterograde tracing with biotinylated dextran amine was used to assess new fiber outgrowth to denervated motor areas.


RESULTS
All treatment groups showed significant motor improvement as compared with control-housed, vehicle-treated animals. However, animals housed in an enriched environment that received amphetamine paired with focused activity sessions performed significantly better than any other treatment group and was the only group to achieve complete motor recovery (ie, reached preoperative performance) by 8 weeks. This recovery was associated with axonal sprouting into deafferentated subcortical areas from contralesional projection neurons.


CONCLUSIONS
This study suggests that, after stroke, short-term pairing of amphetamine with sufficiently focused activity is an effective means of inducing long-term improvement in forelimb motor function. The anatomic data suggests that corticoefferent plasticity in the form of axonal sprouting contributes to the maintenance of motor recovery.
Papadopoulos
Catherine M
CM
Edward Hines, Jr, VA Hospital, Research Service 151, Hines, IL 60141, USA.
Tsai
Shih-Yen
SY
Guillen
Veronica
V
Ortega
Juan
J
Kartje
Gwendolyn L
GL
Wolf
William A
WA
D000662:Amphetamines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004525:Efferent Pathways / Q000187:drug effects / Q000502:physiology; D005552:Forelimb / Q000294:innervation / Q000503:physiopathology; D020439:Growth Cones / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009044:Motor Cortex / Q000187:drug effects / Q000502:physiology; D009069:Movement Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D010291:Paresis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D020318:Rats, Long-Evans; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome
D000662:Amphetamines; D000697:Central Nervous System Stimulants