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, 29 (5), 971-89

Amphetamine-enhanced Motor Training After Cervical Contusion Injury

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Amphetamine-enhanced Motor Training After Cervical Contusion Injury

Laura Krisa et al. J Neurotrauma.

Abstract

Individually, motor training, pharmacological interventions, and housing animals in an enriched environment (EE) following spinal cord injury (SCI) result in limited functional improvement but, when combined, may enhance motor function. Here, we tested amphetamine (AMPH)-enhanced skilled motor training following a unilateral C3-C4 contusion injury on the qualitative components of reaching and on skilled forelimb function, as assessed using single-pellet and staircase reaching tasks. Kinematic analysis evaluated the quality of the reach, and unskilled locomotor function was also tested. Animals receiving AMPH and skilled forelimb training performed better than operated control animals on qualitative reaching, but not on skilled reaching. Those that received the combination treatment and were housed in EE cages showed significantly less improvement in qualitative reaching and grasping. Kinematic analysis revealed a decrease in digit abduction during skilled reaching among all groups, with no differences among groups. Kinematics provided no evidence that improved function was related to improved quality of reach. There was no evidence of neuroprotection in the cervical spinal cord. The absence of evidence for kinematic improvement or neuroprotection suggested that AMPH-enhanced motor training is due primarily to supraspinal effects, an enhancement of attention during skilled motor training, or plasticity in supraspinal circuitry involved with motor control.

Figures

FIG. 1.
FIG. 1.
Enriched environment (EE) housing cage. Multilevel cages allowed animals to transverse ladders, climb through tubes, run in a wheel, practice skilled forelimb reaching in a reaching trough, and forage for food. Food was also placed in different areas of the cage, encouraging the animals to climb.
FIG. 2.
FIG. 2.
Dose-response curves. (A) Locomotor activity is significantly increased in animals that received amphetamine (AMPH) compared to saline. Results are normalized to week 1. No difference was seen among treatment groups or control animals during weeks when no drug was administered (weeks 5 and 9, and 13–17). (B) Animals that received 1.0 mg/kg AMPH performed significantly better during qualitative reaching at weeks 9 and 17 compared to the saline group (p<0.05). Means and standard errors are shown (*p<0.05 for all figures).
FIG. 3.
FIG. 3.
Skilled motor reaching assessment of the right forelimb. (A) Qualitative reaching score. Drug+training animals performed significantly better then saline and drug-only animals on weeks 9 and 17 post-lesion. Training alone was more effective than drug after 1 month with no drug (week 17). (B) The advance, digits open, and pronation phases were enhanced compared to the saline group during week 17. (C) Quantitative reaching was impaired in all groups following injury, but all groups showed an increase in pellet retrieval over time. (D) The staircase-reaching test showed a severe deficit in grasping ability in all groups, with improvement in any group over time (↑ indicates retention period).
FIG. 3.
FIG. 3.
Skilled motor reaching assessment of the right forelimb. (A) Qualitative reaching score. Drug+training animals performed significantly better then saline and drug-only animals on weeks 9 and 17 post-lesion. Training alone was more effective than drug after 1 month with no drug (week 17). (B) The advance, digits open, and pronation phases were enhanced compared to the saline group during week 17. (C) Quantitative reaching was impaired in all groups following injury, but all groups showed an increase in pellet retrieval over time. (D) The staircase-reaching test showed a severe deficit in grasping ability in all groups, with improvement in any group over time (↑ indicates retention period).
FIG. 4.
FIG. 4.
Locomotor measures of the right forelimb. (A) Grid walking (sensorimotor) showed a deficit with a partial recovery by week 5. (B) Forelimb Locomotor Score (FLS) at week 13 showed few deficits (e.g., incomplete toe clearance), with no difference among groups. All animals had normal locomotion function (FLS=17) prior to surgery.
FIG. 5.
FIG. 5.
Enhanced training with enriched environment (EE). Animals that received drug and training and were housed in EE cages performed significantly worse (p<0.05) than animals receiving drug and training and housed in standard cages, in both qualitative (A and B) and staircase (C) reaching. These differences were significant at week 9, and persisted for the remainder of the study. Quantitative reaching displayed no difference among groups, but improved over time (D).
FIG. 5.
FIG. 5.
Enhanced training with enriched environment (EE). Animals that received drug and training and were housed in EE cages performed significantly worse (p<0.05) than animals receiving drug and training and housed in standard cages, in both qualitative (A and B) and staircase (C) reaching. These differences were significant at week 9, and persisted for the remainder of the study. Quantitative reaching displayed no difference among groups, but improved over time (D).
FIG. 6.
FIG. 6.
The number of reach attempts made by the animals at weeks 1 (A) and 13 (B). More attempts were made at week 13 than at week 1 (Saline, control; D, drug only; T, training only; D+T, drug and training; D+T+EE, drug and training in enriched environmental housing; *p<0.05 by Fisher's 2×2 exact test).
FIG. 7.
FIG. 7.
Kinematic analysis of the digit abduction and pronation excursion components of the Whishaw qualitative reach-to-grasp test. (A) Digit abduction was significantly decreased at week 13 in saline controls, drug, drug plus treatment, and drug plus treatment plus enriched environment (EE) animals compared to preoperative measures. (B) All groups showed a significant deficit in digit abduction during week 17. Pronation excursion revealed no difference among groups at weeks 13 and 17 (C and D).
FIG. 7.
FIG. 7.
Kinematic analysis of the digit abduction and pronation excursion components of the Whishaw qualitative reach-to-grasp test. (A) Digit abduction was significantly decreased at week 13 in saline controls, drug, drug plus treatment, and drug plus treatment plus enriched environment (EE) animals compared to preoperative measures. (B) All groups showed a significant deficit in digit abduction during week 17. Pronation excursion revealed no difference among groups at weeks 13 and 17 (C and D).
FIG. 8.
FIG. 8.
(A) Representative cross-section of a cervical dorsolateral contusion. Injury ablates dorsolateral white matter, often produces partial damage to lateral gray matter, and may extend into the ventral-lateral white matter. (B) Paralysis rating conducted 3 days post-lesion showed that animals with a paralysis rating of 3 (highest degree of impairment) had larger lesions than animals rated 1 or 2.

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