Skip to main content Accessibility help

Enhancing Recovery after Stroke with Noradrenergic Pharmacotherapy: A New Frontier?

  • David J. Gladstone (a1) and Sandra E. Black (a1)


Despite much progress in stroke prevention and acute intervention, recovery and rehabilitation have traditionally received relatively little scientific attention. There is now increasing interest in the development of stroke recovery drugs and innovative rehabilitation techniques to promote functional recovery after completed stroke. Experimental work over the past two decades indicates that pharmacologic intervention to enhance recovery may be possible in the subacute stage, days to weeks poststroke, after irreversible injury has occurred. This paper discusses the concept of “rehabilitation pharmacology” and reviews the growing literature from animal studies and pilot clinical trials on noradrenergic pharmacotherapy, a new experimental strategy in stroke rehabilitation. Amphetamine, a monoamine agonist that increases brain norepinephrine levels, is the most extensively studied drug shown to promote recovery of function in animal models of focal brain injury. Further research is needed to investigate the mechanisms and clinical efficacy of amphetamine and other novel therapeutic interventions on the recovery process.

    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Enhancing Recovery after Stroke with Noradrenergic Pharmacotherapy: A New Frontier?
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Enhancing Recovery after Stroke with Noradrenergic Pharmacotherapy: A New Frontier?
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Enhancing Recovery after Stroke with Noradrenergic Pharmacotherapy: A New Frontier?
      Available formats


Corresponding author

Cognitive Neurology Unit, Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, Room A421, Toronto, Ontario, Canada M4N 3M5


Hide All
1. Hill, MD, Hachinski, V. Stroke treatment: time is brain. Lancet 1998;352:1014.
2. Hachinski, V. Relevance of rodent models of stroke. Arch Neurol 1996;53:1070.
3. Stroke Unit Trialists. Organised inpatient (stroke unit) care for stroke. The Cochrane Library, 1999.
4. Kwakkel, G, Wagenaar, RC, Koelman, TW, Lankhorst, GJ, Koetsier, JC. Effects of intensity of rehabilitation after stroke: a research synthesis. Stroke 1997;28:15501556.
5. Kwakkel, G, Wagenaar, RC, Twisk, JWR, Lankhorst, GJ, Koetsier, JC. Intensity of leg and arm training after primary middle-cerebral-artery stroke: A randomized trial. Lancet 1999;354:191196.
6. Goldstein, LB. Restorative neurology: Advances in Pharmacotherapy for Recovery After Stroke. New York: Futura Publishing, 1998.
7. Goldstein, LB. Pharmacologic effects on recovery of neurologic function. In: Lazar, RB, ed. Principles of Neurologic Rehabilitation. New York: McGraw Hill, 1998:565578.
8. Feeney, DM. Rehabilitation pharmacology: noradrenergic enhancement of physical therapy. In: Ginsberg, MD, Bogousslavsky, J, eds. Cerebrovascular Disease. Blackwell Science, 1998:620636.
9. Geldmacher, DS. Enhancing recovery from ischemic stroke. Neurosurg Clin N Am 1997;2:245251.
10. Feeney, DM, Gonzalez, A, Law, WA. Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science 1982;217:855857.
11. Feeney, DM. Amphetamine restores locomotor function after motor cortex injury in the rat. Proc West Pharmacol Soc 1981; 24:1517.
12. Dunbar, GL, Smith, GA, Look, SK, Whalen, RJ. δ-amphetamine attenuates learning and motor deficits following cortical injury in rats. Soc Neurosci Abstr 1989;15:132 (Abstract).
13. Goldstein, LB, Davis, VA. The role of experience on amphetamine facilitated recovery of beam-walking in the rat. Soc Neurosci Abstr 1989;15:69(Abstract).
14. Goldstein, LB, Davis, JN. postlesion practice and amphetamine facilitated recovery of beam-walking in the rat. Restor Neurol Neurosci 1990;2:311314.
15. Goldstein, LB. Amphetamine-facilitated functional recovery after stroke. In: Ginsberg, MD, Dietrich, WD, eds. Cerebrovascular Diseases. New York: Raven Press, 1989:303308.
16. Sutton, RL, Feeney, DM. δ-noradrenergic agonists and antagonists affect recovery and maintenance of beam-walking ability after sensorimotor cortex ablation in the rat. Restor Neurol Neurosci 1992;4:111.
17. Irish, SL, Davis, GW, Barth, TM. A specific behavioral role for norepinephrine in the recovery of locomotor placing following cortical lesions in the rat. Soc Neurosci Abstr 1995;21:170 (Abstract).
18. Goldstein, LB. The influence of lesion size and location on amphetamine facilitated recovery of beam walking in rats. Behav Neurosci 1990;104:320327.
19. Hovda, DA, Fenney, DM. Amphetamine with experience promotes recovery of locomotor function after unilateral frontal cortex injury in the cat. Brain Res 1984;298:358361.
20. Feeney, DM. Amphetamine and apomorphine restore tactile placing after motor cortex injury in the cat. Psychopharmacology 1983;79:6771.
21. Sutton, RL, Hovda, DA, Feeney, DM. Amphetamine accelerates recovery of locomotor function following bilateral frontal cortex ablation in cats. Behav Neurosci 1989;103:837841.
22. Salo, AA, Feeney, DM. Reduction of morbidity, mortality, and lesion size in a rat model of cerebral infarction with amphetamine. Soc Neurosci Abstr 1987;13:1268(Abstract).
23. Stroemer, RP, Kent, TA, Hulsebosch, CE. Amphetamines permanently promote recovery following cortical infarction. Soc Neurosci Abstr 1994;20:186(Abstract).
24. Hurwitz, BE, Dietrich, WD, McCabe, PM, et al. Amphetamine promotes recovery from sensory-motor integration deficit after thrombotic infarction of the primary somatosensory rat cortex. Stroke 1991;22:648654.
25. Dietrich, WD, Alonso, O, Busto, R, et al. Influence of amphetamine treatment on somatosensory function of the normal and infarcted rat brain. Stroke 1990;21:147150.
26. Feeney, DM, Hovda, DA. Reinstatement of binocular depth perception by amphetamine and visual experience after visual cortex ablation. Brain Res 1985;342:352356.
27. Hovda, DA, Feeney, DM. Haloperidol blocks amphetamine-induced recovery of binocular depth perception after bilateral visual cortex ablation in cats. Proc West Pharmacol Soc 1985;28:209211.
28. Hovda, DA, Sutton, RL, Feeney, DM. Amphetamine-induced recovery of visual cliff performance after bilateral visual cortex ablation in cats: measurement of depth perception thresholds. Behav Neurosci 1989;103:574584.
29. Cornwell, P. Performance on the visual cliff by cats with marginal gyrus lesions. Physiol Psychol 1976;90:9961010.
30. Boyeson, MG, Feeney, DM. Adverse effects of catecholaminergic agonists and antagonists on recovery of locomotor ability following unilateral cerebellar ablations. Restor Neurol Neurosci 1991;3:227233.
31. Mintz, M, Tomer, R. Exposure to amphetamine after substantia nigra lesion interferes with the process of behavioral recovery. Pharmacol Biochem Behav 1986;25:13071311.
32. Goldstein, LB. Pharmacology of recovery after stroke. Stroke 1990;21(suppl 3):III–139--III–142.
33. Prasad, MR, Ramaiah, C, McIntosh, TR, et al. Regional levels of lactate and norepinephrine after experimental brain injury. J Neurochem 1994;63:10861094.
34. Dunn-Meynell, A, Pan, S, Levin, BE. Focal traumatic brain injury causes widespread reductions in rat brain norepinephrine turnover from 6 to 24 hr. Brain Res 1994;660 :8895.
35. Robinson, RG, Shoemaker, WJ, Schlumpf, M, Coyle, JT. Effect of experimental cerebral infarction in rat brain on catecholamines and behavior. Nature 1975;255:332334.
36. Robinson, RG. Differential behavioral and biochemical effects of right and left hemispheric cerebral infarction in the rat. Science 1979;205:707710.
37. Finklestein, S, Campbell, A, Baldessarini, RJ, Moya, K, Haber, SN. Late changes in cerebral monoamine metabolism following focal ventrolateral cerebrocortical lesions. Brain Res 1985;344:205210.
38. Boyeson, MG, Feeney, DM. Striatal dopamine after cortical injury. Exp Neurol 1985;89:479483.
39. Meyer, JS, Stoica, E, Pascu, I, Shimazu, K, Hartmann, A. Catecholamine concentrations in CSF and plasma of patients with cerbral infarction and hemorrhage. Brain 1973;96:277288.
40. Brown, RM, Carlson, A, Ljungren, BL, Seisjo, BK, Snider, SR. Effect of ischemia on monoamine metabolism in the brain. Acta Physiol Scand 1974;90:789791.
41. Cohen, HP, Woltz, AG, Jacobson, RL. Catecholamine content of cerebral tissue after occlusion or manipulation of middle cerebral artery in cats. J Neurosurg 1975;43:3236.
42. Prasad, MR, Tzigaret, CM, Smith, D, Soares, H, McIntosh, TK. Decreased alpha 1-adrenergic receptors after experimental brain injury. J Neurotrauma 1992;9:269279.
43. Levin, BE, Pan, S, Dunn-Meynell, A. Chronic alterations in rat brain alpha-adrenoreceptors following traumatic brain injury. Restor Neurol Neurosci 1994;7:512.
44. Robinson, RG, Shoemaker, WJ, Schlumpf, M. Time course of changes in catecholamines following right hemisphere cerebral infarction in the rat. Brain Res 1980;181:202208.
45. Boyeson, MG, Feeney, DM. Intraventricular norepinephrine facilitates motor recovery following sensorimotor cortex injury. Pharm Biochem Behav 1990;35:497501.
46. Feeney, DM, Weisend, MP, Kline, AE. Noradrenergic pharmaco therapy, intracerebral infusion and adrenal transplantation promote functional recovery after cortical damage. J Neurotransplantation 1994;4:199214.
47. Boyeson, MG, Harmon, RL, Jones, JL. Comparative effects of fluoxetine, amitriptyline and serotonin on functional motor recovery after sensorimotor cortex injury. Am J Phys Med Rehabil 1994;73:7683.
48. Goldstein, LB, Poe, HV, Davis, JN. An animal model of recovery of function after stroke: Facilitation of recovery by an a2-Adrenergic receptor antagonist. Ann Neurol 1989;26:157 (Abstract).
49. Feeney, DM, Sutton, RL. Catecholamines and recovery of function after brain damage. In: Sabel, BA, Stein, DG, eds. Pharmacological Approaches to the Treatment of Brain and Spinal Cord Injury. New York: Plenum, 1988:121142.
50. Hovda, DA. Phentermine accelerates recovery of function after motor cortex injury in rats and cats. FASEB J 1983;42:1157.
51. Kline, AE, Chen, MJ, Tso-Olivas, DY, Feeney, DM. Methylphenidate treatment following ablation-induced hemiplegia in rat: Experience during drug action alters effects on recovery of function Pharm Biochem Behav 1994; 48:773779.
52. Chen, MJ, Sutton, RL, Feeney, DM. Recovery of function following brain injury in rat and cat: Beneficial effects of phenylpropanol-amine. Soc Neurosci Abstr 1986;12:881 (Abstract).
53. Boyeson, MG, Harmon, RL. Effects of trazadone and desipramine on motor recovery in brain-injured rats. Am J Phys Med Rehabil 1993;72:286293.
54. Goldstein, LB, Coviello, A, Miller, GD, Davis, JN. Norepinephrine depletion impairs motor recovery following sensorimotor cortex injury in the rat. Restore Neurol Neurosci 1991;3:4147.
55. Boyeson, MG, Callister, TR, Cavazos, JE. Biochemical and behavioral effects of a sensorimotor cortex injury in rats pretreated with the noradrenergic neurotoxin DSP-4. Behav Neurosci 1992;106:964973.
56. Goldstein, LB, Davis, JN. Clonidine impairs recovery of beam walking after a sensorimotor cortex lesion in the rat. Brain Res 1990;508:305309.
57. Stephens, J, Goldberg, G, Demopoulos, JT. Clonidine reinstates deficits following recovery from sensorimotor cortex lesion in rats. Arch Phys Med Rehabil 1986;67:666667 (Abstract).
58. Feeney, DM, Westerberg, VS. Norepinephrine and brain damage: alpha noradrenergic pharmacology alters functional recovery after cortical trauma. Can J Psychol 1990;44:233252.
59. Hovda, DA, Feeney, DM, Salo, AA, Boyeson, MG. Phenoxy benzamine but not haloperidol reinstates all motor and sensory deficits in cats fully recovered from sensorimotor cortex ablations. Soc Neurosci Abstr 1983;9:1002 (Abstract).
60. Crisostomo, EA, Duncan, PW, Propst, M, Dawson, DV, Davis, JN. Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Ann Neurol 1988;23:9497.
61. Reding, M, Solomon, B, Borucki, SJ. Effect of dextroamphetamine on motor recovery after stroke. Neurology 1995;45:A222(Abstract).
62. Borucki, SJ, Langberg, J, Reding, M. The effect of dextroampheta mine on motor recovery after stroke. Neurology 1992;42:329 (Abstract).
63. Walker-Batson, D, Smith, P, Curtis, S, Unwin, H, Greenlee, R. Amphetamine paired with physical therapy accelerates motor recovery after stroke. Stroke 1995;26:22542259.
64. Walker-Batson, D. Pharmacotherapy in the treatment of aphasia. In: Goldstein, LB, ed. Restorative Neurology: Advances in Pharmacotherapy for Recovery after Stroke. New York: Futura Publishing, 1998:257270.
65. Walker-Batson, D, Devous, MD Sr, Curtis, S, Unwin, DH, Greenlee, RG. Response to amphetamine to facilitate recovery from aphasia subsequent to stroke. Clin Aphasiol 1990;20:137143.
66. Walker-Batson, D, Unwin, H, Curtis, S. Use of amphetamine in the treatment of aphasia. Restor Neurol Neurosci 1992;4:4750.
67. Small, SL. Pharmacotherapy of aphasia. A critical review. Stroke 1994;25:12821289.
68. Feeney, DM. From laboratory to clinic: Noradrenergic enhancement of physical therapy for stroke or trauma patients. In: Freund, HJ, Sabel, BA and Witte, OW. Advances in Neurology. 1997. Philadelphia: Lippincott-Raven Publishers, 383394.
69. Smith, P, Unwin, H, Curtis, S, Walker-Batson, D. Negligible effects of amphetamine administration in stroke rehabilitation. Neurology. 1999;52:8081.(Abstract).
70. Grade, C, Redford, B, Chrostowski, J, Toussaint, L, Blackwell, B. Methylphenidate in early poststroke recovery: A double-blind, placebo-controlled study. Arch Phys Med Rehabil 1998;79:10471050.
71. Goldstein, LB, Davis, JN. Physician prescribing patterns following hospital admission for ischemic cerebrovascular disease. Neurology 1988;38:18061809.
72. Goldstein, LB. Prescribing of potentially harmful drugs to patients admitted to hospital after head injury. J Neurol Neurosurg Psychiatry 1995;58:753755.
73. Goldstein, LB. Influence of common drugs and related factors on stroke outcome. Curr Opin Neurol 1997;10:5257.
74. Goldstein, LB. Potential effects of common drugs on stroke recovery. Arch Neurol 1999;55:454456.
75. Goldstein, LB. The Sygen in acute stroke study investigators. Common drugs may influence motor recovery after stroke. Neurology 1995;45:865871.
76. Goldstein, LB, Matchar, DB, Morgenlander, JC, Davis, JN. Influence of drugs on the recovery of sensorimotor function after stroke. J Neurol Rehab 1990;4:137144.
77. Graham, GD, Ahmed, W, Davis, LE, et al. Effects of commonly prescribed medications on stroke recovery: a TOAST study analysis. Stroke 1999;30:236(Abstract).
78. Goldstein, LB, Davis, JN. Restorative neurology. Drugs and recovery following stroke. Stroke 1990;25:1924.
79. Feeney, DM. Mechanisms of noradrenergic modulation of physical therapy: effects on functional recovery after cortical injury. In: Goldstein, LB, ed. Restorative Neurology: Advances in Pharmacotherapy for Recovery after Stroke. New York: Futura, 1998:3578.
80. Feeney, DM, Baron, JC. Diaschisis. Stroke 1986;17:817830.
81. Von Monakow, C. Diaschisis. In: Pribram, KH, ed. Brain and Behavior, Mood, States and Mind. Baltimore, Maryland: Penguin Book, 1969:2736.
82. Nguyen, DK, Botez, MI. Diaschisis and neurobehavior. Can J Neurol Sci 1998;25:512.
83. Feeney, DM. Pharmacologic modulation of recovery after brain injury: a reconsideration of diaschisis. J Neurol Rehab 1991;5:113128.
84. Sutton, RL, Feeney, DM. Noradrenergic pharmacotherapy and functional recovery after cortical injury. In: Illis, LS, ed. Neurological Rehabilitation. England: Blackwell, 1994:469480.
85. Boyeson, MG, Krobert, KA. Cerebellar norepinephrine infusions facilitate recovery after sensorimotor cortex injury. Brain Res Bull 1992;29:435439.
86. Bowler, JV, Costa, DC, Jones, BE. High resolution SPECT, small deep infarcts and diaschisis. J R Soc Med 1992;85:142146.
87. Seil, FJ. Recovery and repair issues after stroke from the scientific perspective. Curr Opin Neurol 1997;10:4951.
88. Johansson, BB. Brain plasticity and stroke rehabilitation: the Willis lecture. Stroke 2000;31:223230.
89. Lee, RG, van Donkelaar, P. Mechanisms underlying functional recovery following stroke. Can J Neurol Sci 1995;22:257263.
90. Chollet, F, Weiller, C. Imaging recovery of function following brain injury. Curr Opin Neurobiol 1994;4:226230.
91. Cramer, SC, Nelles, G, Benson, RR, et al. A functional MRI study of subjects recovered from hemiparetic stroke. Stroke 1997;28: 25182527.
92. Silvestrini, M, Cupini, LM, Placidi, F, Diomedi, M, Bernardi, G. Bilateral hemispheric activation in the early recovery of motor function after stroke. Stroke 1998;29:13051310.
93. Cao, Y, D’Olhaberriague, L, Vikingstad, EM, Levine, SR, Welch, KMA. Pilot study of functional MRI to assess cerebral activation of motor function after poststroke hemiparesis. Stroke 1998;29:112122.
94. Chollet, F, DiPiero, V, Wise, RJS, et al. The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann Neurol 1991;29:6371.
95. Nudo, RJ, Wise, BM, SiFuentes, F, Milliken, GW. Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 1996;272:17911794.
96. Stroemer, RP, Kent, TA, Hulsebosch, CE. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. Stroke 1998;29:23812395.
97. Nudo, RJ, Milliken, GW. Reorganization of movement representations in primary motor cortex following focal ischemic infarcts in adult squirrel monkeys. J Neurophysiol 1996;75:21442149.
98. Dobkin, BH. Neurorehabilitation: greater plasticity through chemicals and practice. Neurology Network Commentary 1998;2:171174.
99. Kozlowski, DA, James, DC, Schallert, T. Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci 1996;16:47764786.
100. Stroemer, RP, Kent, TA, Hulsebosch, CE. Neocortical neural sprouting, synaptogensis, and behavioral recovery after neocortical infarction in rats. Stroke 1995;26:21352144.
101. Kawamata, T, Ren, J, Chan, TCK, Charette, M, Finklestein, SP. Intracisternal osteogenic protein-1 enhances functional recovery following focal stroke. Neuroreport 1998;9:14411445.
102. Kawamata, T, Alexis, NE, Dietrich, WD, Finklestein, SP. Intracisternal basic fibroblast growth factor (bFGF) enhances behavioral recovery following focal cerebral infarction in the rat. J Cereb Blood Flow Metab 1996;16:542547.
103. Dietrich, WD, Alonso, O, Busto, R, Ginsberg, MD. The effect of amphetamine on functional brain activation in normal and postinfarcted rat. Stroke 1990;21:147150.
104. Gold, P, Delanoy, R, Merrin, J. Modulation of long-term potentiation by peripherally administered amphetamine and epinephrine. Brain Res 1984;305:103107.
105. Classen, J, Liepert, J, Wise, SP, Hallett, M, Cohen, LG. Rapid plasticity of human cortical movement representation induced by practice. J Neurophysiol 1998;79:11171123.
106. Cohen, LG, Davis, B. Pharmacological enhancement of plasticity in the human motor cortex. Neurology 1999;52:A15(Abstract).
107. Loubinoux, I, Boulanlouar, K, Ranjeva, JP, et al. Cerebral fRMI activation modulated by a single dose of the monoamines neurotransmission enhancers fluoxetine and fenozolone during hand sensorimotor tasks. Neurology 1999;52:A15(Abstract).
108. Mattay, VS, Berman, KF, Ostrem, JL, et al. Dextroamphetamine enhances “Neural network-specific” physiological signals: a positron-emission tomography rCBF study. J Neurosci 1996;16: 48164822.
109. Uftring, SJ, Chu, D, McCandless, C, et al. An fMRI study of the efffects of amphetamine on brain activity. Neuroimage 1999;(Abstract)

Enhancing Recovery after Stroke with Noradrenergic Pharmacotherapy: A New Frontier?

  • David J. Gladstone (a1) and Sandra E. Black (a1)


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed