ENHANCED NEOCORTICAL NEURAL SPROUTING, SYNAPTOGENESIS, AND BEHAVIORALRECOVERY WITH D-AMPHETAMINE THERAPY AFTER NEOCORTICAL INFARCTION IN RATS

Background and Purpose-D-Amphetamine administration increases behavior al recovery after various cortical lesions including cortical ablation s, contusions, and focal ischemia in animals and after stroke in human s. The purpose of the present study was to test the enhanced behaviora l recovery and increased expression of proteins involved in neurite gr owth and synaptogenesis in D-amphetamine-treated rats compared with ve hicle-treated controls after a focal neocortical infarct. Methods-Unil ateral neocortical ischemia was induced in male spontaneously hyperten sive Wistar rats (n=s per time point per group) by permanently occludi ng the distal middle cerebral artery and ipsilateral common carotid ar tery in 2 groups of rats: D-amphetamine treated (2 mg/kg LP injections ) and vehicle treated (saline IP injections). To determine the spatial and temporal distribution of neurite growth and/or synaptogenesis, gr owth-associated protein (GAP-43), a protein expressed on axonal growth cones, and synaptophysin, a calcium-binding protein found on synaptic vesicles, were examined by immunohistochemical techniques, and both d ensity and distribution of reaction product were measured. Since the r esulting infarction included a portion of the forelimb neocortex, beha vioral assessments;of forelimb function using the foot-fault test of H ernandez and Schallert were performed on the same rats used for immuno histochemical studies during the period of drug action and 24 hours la ter. A Morris water maze and other indices of behavioral assays were a lso measured similarly. Recovery times were 3, 7, 14, 30, and 60 days postoperatively. Results-Both GAP-43 and synaptophysin proteins demons trated statistically significant increases in density and distribution of immunoreaction product as determined by optical density measuremen ts in the neocortex of the infarcted group treated with D-amphetamines compared with vehicle-treated infarcted controls. The GAP-43 was elev ated to statistically significant levels in forelimb, hindlimb, and pa rietal neocortical regions ipsilateral to the infarction only at days 3, 7, and 14. By contrast, the synaptophysin demonstrated no statistic ally significant changes in expression at 3 or 7 days but demonstrated statistically significant increases at 14, 30, and 60 days in the for elimb, hindlimb, and parietal neocortical regions ipsilateral to the i nfarction as well as increased distribution in the contralateral parie tal neocortex. Behavioral assessment of forelimb function indicated th at improved recovery of forelimb placement on the side contralateral t o the infarction was statistically significant in the D-amphetamine-tr eated group compared with the vehicle-treated group (P<0.025). Spatial memory, as measured with the Morris water maze, worsened in the vehic le-treated group compared with the D-amphetamine-treated group at 60 d ays (P<0.025). Conclusions-These data support the occurrence of neurit e growth followed by synaptogenesis in the neocortex in a pattern that corresponds both spatially and temporally with behavioral recovery th at is accelerated by D-amphetamine treatment. While the specific mecha nisms responsible for D-amphetamine-promoted expression of proteins in volved in neurite growth and synaptogenesis and of enhanced behavioral recovery are not known, it is suggested that protein upregulation occ urs as a result of functional activation of pathways able to remodel i n response to active behavioral performance.