Video Illustrating Transient Reinstatement of Hemiplegic Symptoms In "Recovered" Rats by Blockade of alpha 1-Noradrenergic Synaptic Transmission


Reinstatement of Symptoms

After unilateral ablation, trauma, or an infarct involving the sensorimotor cortex there is a hemiplegia that "spontaneously" recovers in one or two weeks in the rat and is best seen by having the animal attempt to traverse a narrow beam.  The hemiplegic animal fails to place the contralateral limbs on the surface of the beam, especially the hindlimb.  During locomotion by hemiplegic animals the contralateral hindlimb is dragged while beam walking is accomplished primarily by using the ipsilateral limbs.  

This video illustrates the importance of alpha 1-Noradrenergic (NA)  transmission for maintaining recovery of function following cortical damage.  After an animal has recovered from hemiplegic symptoms produced by sensorimotor cortex injury this "recovered state" is vulnerable to disruption by blockade of alpha 1-NA activity.  The initial symptoms can be transiently reinstated by certain drugs in the recovered rat at least 6 months after " recovery".  Administration of selective alpha 1-NA receptor antagonists, such as phenoxybenzamine or prazosin (shown in the video) or by clonidine, an alpha 2-NA agonist which also reduces NA release, all transiently reinstate hemiplegic symptoms.  This video initally shows a "recovered" rat four months after focal sensorimotor cortex contusion displaying normal beam walking performance.  The video then shows reinstatement of symptoms in this "recovered" rat after receiving 4 mg/kg (i.p.) of prazosin.  Within 30 minutes after prazosin administration, the rat who had recovered from all hemiplegic symptoms four months earlier does not place the contralateral limbs on the beam surface (especially the hindlimb) during locomotion as do "recovered" or normal rats.  The hemiplegia observed during the first weeks after injury that had "recovered" three-four months earlier, reappears for 2-3 hours.  A low dose (2 mg/kg) of prazosin has little effect on beam walking in normal rats but reinstates hemiplegia in recovered injured animals.  In normal animals higher doses of prazosin may disrupt beam walking but have bilateral effects quite unlike hemiplegia.  The unilateral symptoms illustrated in this video are typical of reinstatement of hemiplegic deficits in recovered rats.  Reinstatement is not due to a nonspecific soporific drug effect since the deficits reappear only in the limbs contralateral to the cortical injury, and do not occur after a sedating dose of pentobarbital.  The reinstatement by alpha 1-NA does not weaken with time after injury as expected.  Dose-response studies show no difference in degree of reinstatement at 1-6 months after injury.  The degree of reinstatement is highly correlated with the severity of the initial deficit (for the high dose of prazosin and beam walk reinstatement scores at 1 month after injury; r = .99).  These data clearly indicate that recovery of some symptoms is a fragile state for a prolonged time after symptoms are no longer apparent.  Lastly, when these drugs are administered early (one day in the rat) after brain injury, they also slow spontaneous recovery.  The data describing these effects are reported in publications from different laboratories listed in the references below (1, 2, 3, 4). Reinstatement has been reported in several species and has implications for the selection of drugs in the management of symptoms in patients with brain injury from stroke or trauma. I thank Debra Stibick for assistance in making this video.

Importance for patients with brain damage from stroke or cerebral trauma

After patients are admitted to a hospital for stroke, clonidine, prazosin, and other drugs, reported harmful for recovery from hemiplegia in laboratory studies, are frequently prescribed for other medical problems such as hypertension (5). The adverse effects on recovery of these and other drugs reported in laboratory studies have also been described for recovery in hemiplegic stroke patients (6) and also slow recovery of aphasia (7, 8).  This data and the mechanisms involved in both the beneficial and harmful effects of NA on functional recovery has been reviewed (9, 10).


1. Feeney, D.M. and Westerberg, V. S. Norepinephrine and brain damage: Alpha noradrenergic pharmacology alters functional recovery after cortical trauma. Canadian Journal of Psychology, 1990,
44, 233-252.
2. Sutton, R.L. and Feeney, D.M. Alpha-noradrenergic agonists and antagonists affect recovery and maintenance of beam-walking ability after sensorimotor cortex ablation in the rat. Restorative Neurology and Neuroscience, 4, 1-11, 1992.
3. Feeney, D.M. From laboratory to clinic: Noradrenergic Enhancement of Physical Therapy for Stroke or Trauma patients. In Freund, H.-J., Sabel, B.A. and Witte, O.W., (Editors) Brain Plasticity; Advances in Neurology, 73, pg. 383-394, Lippencott-Raven Publishers, Philadelphia, 1997.
4. Goldstein LB, Davis JN.  Clonidine impairs recovery of beam-walking after a sensorimotor cortex lesion in the rat.  Brain Res 1990;508:305-309
5.  Goldstein, LB, Davis,JN  Physician prescribing patterns following hospital admission for ischemic cerebrovascular disease.  Neurology, 1988,38;1806-1899.
6.  Goldstein LB, SASS Study Investigators.  Common drugs may influence motor recovery after stroke.  Neurology 1995;45:865-871
7.  Porch BE, Feeney DM.  Effects of antihypertensive drugs on recovery from aphasia.  Proc Clin Aphasia Conf  1986;16:309-314.
8.  Feeney, D.M. From laboratory to clinic: Noradrenergic Enhancement of Physical Therapy for Stroke or Trauma patients. In Freund, H.-J., Sabel, B.A. and Witte, O.W., (Editors) Brain Plasticity; Advances in Neurology, 73, pg. 383-394, Lippencott-Raven Publishers, Philadelphia, 1997.
9.  Feeney, D.M., Pharmacologic Modulation of recovery after brain injury:  a reconsideration of diaschisis. Journal of Neurologic Rehabilitation, 5, 113-128, 1991.
10.  Feeney, D. M. Rehabilitation Pharmacology: Noradrenergic Enhancement of Physical Therapy.  In: Ginsberg, M. and Bogousslavsky, J. (Editors) Cerebrovascular Diseases, Vol. I. Blackwell Scientific Press Cambridge MA (In Press.).