One day of motor training with amphetamine impairs motor recovery following spinal cord injury Jamie K. Wong a, b , Oswald Steward a, b, c, d, ⁎ a Department of Neurobiology & Behavior, University of California at Irvine, Irvine, CA 92697, USA b Reeve-Irvine Research Center, University of California at Irvine, Irvine, CA 92697, USA c Departments of Anatomy & Neurobiology and Neurosurgery, University of California at Irvine, Irvine, CA 92697, USA d Center for the Neurobiology of Learning and Memory, University of California at Irvine, Irvine, CA 92697, USA abstract article info Article history: Received 12 April 2011 Revised 29 May 2011 Accepted 8 August 2011 Available online 10 November 2011 It has previously been reported that a single dose of amphetamine paired with training on a beam walking task can enhance locomotor recovery following brain injury (Feeney et al., 1982). Here, we investigated whether this same drug/training regimen could enhance functional recovery following either thoracic (T9) or cervical (C5) spinal cord injury. Different groups of female Sprague–Dawley rats were trained on a beam walking task, and in a straight alley for assessment of hindlimb locomotor recovery using the BBB locomotor scale. For rats that received C5 hemisections, forelimb grip strength was assessed using a grip strength meter. Three separate experiments assessed the consequences of training rats on the beam walking task 24 h following a thoracic lateral hemisection with administration of either amphetamine or saline. Beginning 1 h following drug administration, rats either received additional testing/retraining on the beam hourly for 6 h, or they were returned to their home cages without further testing/retraining. Rats with thoracic spinal cord injuries that received amphetamine in conjunction with testing/retraining on the beam at 1 day post injury (DPI) exhibited significantly impaired recovery on the beam walking task and BBB. Rats with cervical spinal cord injuries that received training with amphetamine also exhibited significant impairments in beam walking and locomotion, as well as impairments in gripping and reaching abilities. Even when administered at 14 DPI, the drug/training regimen significantly impaired reaching ability in cervical spinal cord injured rats. Impairments were not seen in rats that received amphetamine without training. Histological analyses revealed that rats that received training with amphetamine had significantly larger lesions than saline controls. These data indicate that an amphetamine/training regimen that improves recovery after cortical injury has the opposite effect of impairing recovery following spinal cord injury because early training with amphetamine increases lesion severity. © 2011 Elsevier Inc. All rights reserved. Introduction Following injury to the central nervous system, there is typically some degree of spontaneous functional recovery that occurs over time. Following thoracic spinal cord injury in rats, spontaneous recovery of locomotor function usually reaches a plateau by several weeks post injury (Basso et al., 1995). In spinal cord injured people, spontaneous recovery may begin days to weeks following injury and can continue for months to years (Raineteau and Schwab, 2001). Spontaneous recovery has been attributed to different forms of neuroplastic changes including synaptic and circuit alterations. Indeed, following a thoracic lateral hemisection, there is a correlation between the degree of synaptic plasticity and axonal sprouting that occurs and the degree of spontaneous functional recovery that is observed (Ballermann and Fouad, 2006; Gulino et al., 2007). Given this, it is of interest to identify therapeutically relevant interventions that could enhance plasticity and/or recovery of function. There is considerable evidence that training enhances recovery, often in a task specific fashion. For example, cats with complete spinal transections that receive locomotor training on a treadmill can learn to support their weight with their hindlimbs and exhibit stepping behavior on the treadmill. These results demonstrate that central pattern generators in the spinal cord can undergo dramatic plastic changes (Lovely et al., 1986). Additionally, rats that are given an opportunity to exercise on a running wheel following thoracic hemisection injuries exhibit increased levels of brain-derived neurotrophic factor (BDNF), synapsin-1, and growth-associated protein 43 (GAP-43), which can play a role in different forms of synaptic remodeling (Ying et al., 2005). Nevertheless, enhanced recovery depends on the nature of the running activity (Engesser-Cesar et al., 2005). Following brain injury, voluntary wheel running and treadmill running have been reported to increase Experimental Neurology 233 (2012) 693–707 ⁎ Corresponding author at: 1105 GNRF, 837 Health Sciences Dr. University of California at Irvine, Irvine, CA 92697, USA. E-mail address: osteward@uci.edu (O. Steward). 0014-4886/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2011.08.011 Contents lists available at SciVerse ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr