Neurotransmitters and Motor Activity: Effects on Functional
Recovery after Brain Injury
Larry B. Goldstein
Department of Medicine (Neurology), Duke Center for Cerebrovascular Disease, Duke University, Durham, North Carolina; and
Durham Department of Veterans Affairs Medical Center, Durham, North Carolina
Summary: There are complex relationships among behavioral
experience, brain morphology, and functional recovery of an
animal before and after brain injury. A large series of experi-
mental studies have shown that exogenous manipulation of
central neurotransmitter levels can directly affect plastic
changes in the brain and can modulate the effects of experience
and training. These complex relationships provide a formidable
challenge for studies aimed at understanding neurotransmitter
effects on the recovery process. Experiments delineating nore-
pinephrine-modulated locomotor recovery after injury to the
cerebral cortex illustrate the close relationships among neuro-
transmitter levels, brain plasticity, and behavioral recovery.
Understanding the neurobiological processes underlying recov-
ery, and how they might be manipulated, may lead to novel
strategies for improving recovery from stroke-related gait im-
pairment in humans. Key Words: Stroke, motor function, brain
injury, norepinephrine, recovery.
Impaired walking after stroke is associated both with
higher levels of disability and with compromised levels
of social functioning. Depending on the level of assis-
tance required, this particular deficit can lead to great
increases in caregiver burden and so may necessitate the
patient’s residence in a formal assisted-living environ-
ment. Effective strategies aimed at improving poststroke
gait impairments would help mitigate its functional and
Much has been learned about the immediate response
of the brain to stroke-related injury, as well as its poten-
tial for plasticity during the recovery period. Understand-
ing the roles of specific neurotransmitters as modulators
of the recovery process could lead to effective poststroke
EFFECT OF EXPERIENCE AND TRAINING
ON FUNCTIONAL LOCOMOTOR RECOVERY
IN ANIMAL MODELS
Numerous studies in laboratory animals show that en-
vironmental complexity can have a direct impact on an-
atomical brain plasticity.1Housing in complex environ-
ments is associated with overall and regionally specific
increases in brain weight, cortical depth, hippocampal
thickness, callosal size, and cortical glial density1and
has effects on both neuronal morphology1,2and connec-
tivity.3It has also long been recognized that housing
animals in complex environments (as opposed to a stan-
dard cage), either before or after brain injury, can lead to
less severe neurological deficits and more favorable out-
comes,4–6although some debate remains as to whether
this represents true recovery or enhancement of compen-
satory behavioral strategies.1
In addition to general environmental factors, a large
number of laboratory studies also show the importance
of training after brain injury for functional motor recov-
ery.2,7,8As summarized in these detailed reviews, exer-
cise can increase levels of neurotrophic factors such as
brain-derived neurotrophic factor (BDNF), enhance neu-
rogenesis, and improve learning. Rehabilitative training
is associated with specific improvements in motor func-
tion after cortex injury in several behavioral para-
digms,9–14particularly when this training is coupled with
housing in complex environments.12,13
Experimental studies in squirrel monkeys suggest that
repetitive use of the impaired hand is required for main-
tenance of the spared portion of the hand representation
after motor cortex infarction.15Overuse of the affected
limb during vulnerable periods after experimental brain
Address correspondence and reprint requests to: Larry B. Goldstein,
M.D., Director, Duke Center for Cerebrovascular Disease, Box 3651,
Duke University Medical Center, Durham, NC 27710. E-mail:
NeuroRx?: The Journal of the American Society for Experimental NeuroTherapeutics
Vol. 3, 451–457, October 2006 © The American Society for Experimental NeuroTherapeutics, Inc.
injury is, however, associated with both exacerbation of
the underlying brain damage, and in some cases, poorer
sensorimotor performance.16–22In ischemia models,
functional outcome is improved despite exacerbation
of injury with exercise begun immediately after the
injury.20Delaying training for longer periods can di-
minish this effect.13Intensive training after the first 3
to 5 days after focal brain injury does not exacerbate
lesion size or negatively affect outcome.11,14
Based on this extensive literature, it is clear that there
are complex relationships among the behavioral experi-
ence, brain morphology, and functional recovery of an
animal before and after brain injury. These various pro-
cesses may affect specific neurotransmitter levels, which
may in turn affect brain plasticity. Exogenous manipu-
lation of central neurotransmitter levels, however, can
directly affect plastic changes in the brain that could
modulate the effects of experience and training. These
complex interrelationships provide a formidable chal-
lenge for studies aimed at understanding neurotransmit-
ter effects on locomotor recovery.
EFFECT OF NOREPINEPHRINE ON NEURAL
A large body of work has focused on norepinephrine-
modulated locomotor recovery after brain injury, illus-
trating the close relationships among neurotransmitter
levels, brain plasticity, and behavior, For example, nor-
epinephrine has been implicated in trophic changes in the
central nervous system.23Local infusion of 6-hydroxy-
dopamine, which depletes central norepinephrine, blocks
the effects of monocular light deprivation in kittens.
Local infusion of norepinephrine reinstates plasticity in
animals that are no longer sensitive to this insult. In-
creases in both growth-associated protein 43 and synap-
tophysin immunostaining in the ipsilateral and contralat-
eral cerebral hemispheres, as well as other brain areas,
have been associated with amphetamine given after uni-
lateral sensorimotor cortex injury in rats.24
Norepinephrine and behavioral recovery
Pharmacological studies. Numerous experimental
studies provide evidence supporting the role of norepi-
nephrine as a modulator of behavioral motor recovery
after injury to the motor cortex. Feeney and coworkers25
first reported that the administration of a single dose of
d-amphetamine the day after a unilateral sensorimotor
cortex injury in the rat results in an enduring enhance-
ment of motor recovery. This group later extended the
observation to other species and other behavioral deficits.
For example, postlesion treatment with amphetamine
also enhances motor recovery in cats with unilateral or
bilateral frontal cortex ablations26,27and reinstates ste-
reoscopic vision in cats with bilateral visual cortex
Although amphetamine may influence the release of
a variety of neurotransmitters, several lines of evi-
dence suggest that its effect on recovery is related to
enhanced release of central norepinephrine. First, di-
rect intraventricular infusion of norepinephrine (but
not dopamine) mimics the effect of amphetamine.30In
addition, pharmacological studies show that the im-
pact on recovery of other adrenergic agonists and an-
tagonists can be predicted based on their effects on the
release of norepinephrine from noradrenergic termi-
nals. Both yohimbine and idazoxan (centrally acting
?2-adrenergic receptor antagonists) increase norepi-
nephrine release and enhance motor recovery when
administered to rats as a single dose after unilateral
sensorimotor cortex injury.31,32Clonidine, a centrally
acting ?2-adrenergic receptor agonist that decreases
norepinephrine release, has a prolonged detrimental
effect on motor recovery in rats and reinstates motor
deficits when given to animals that had recovered mo-
tor function.33,34Prazosin and phenoxybenzamine,
centrally acting ?1-adrenergic receptor antagonists,
are also harmful.34–36Coadministration of the butyro-
phenone haloperidol blocks amphetamine-promoted
motor recovery in rats and impairs motor recovery
when given alone.25Haloperidol also blocks amphet-
amine-facilitated visual recovery in visually decorti-
cated cats.29,37Haloperidol, fluanisone, and droperidol
each transiently reinstate motor deficits in recovered
Because haloperidol is a dopamine receptor antag-
onist, these later experiments might be considered as
providing evidence for a dopaminergic effect on motor
recovery after brain injury; however, haloperidol is
also a noradrenergic receptor antagonist. Radioligand
binding studies show that haloperidol is a marginally
more potent ?1-adrenergic receptor antagonist than
clozapine (Kd6.1 versus 9 nM, respectively), but clo-
zapine is a significantly more potent ?2-adrenergic
receptor antagonist than haloperidol (Kd160 versus
3800 nM, respectively). As expected, dose–effect ex-
periments found that haloperidol had increasingly det-
rimental effects on post–brain injury motor recovery
with increasing dose.39In contrast, clozapine facili-
tated recovery at low dose (an ?2-adrenergic receptor
antagonist effect) but impaired recovery at higher
doses (an ?1-adrenergic receptor antagonist effect;
FIG. 1). Thus, the dose-related effect of clozapine on
recovery (facilitory at low doses and detrimental at
higher doses) and the harmful effects of haloperidol
are entirely predictable based on a noradrenergically
Lesioning studies. Consistent with the pharmacolog-
ical data, several additional lines of evidence suggest the
LARRY B. GOLDSTEIN452
NeuroRx?, Vol. 3, No. 4, 2006
importance of norepinephrine as a modulator of motor
recovery after brain injury. The neurotoxin DSP-4 [N-(2-
chloroethyl)-N-ethyl-2-bromobenzylamine selectively de-
stroys central noradrenergic neurons. Pretreatment with
DSP-4 impaired motor recovery in rats after a subsequent
injury to the cerebral cortex, but the norepinephrine deple-
tion had no effect on locomotor activity in rats without a
cortical lesion.40,41The pontine nucleus locus ceruleus is
the major source of noradrenergic projection fibers to the
cerebral cortex.42–44Cortical damage elicits changes in
the norepinephrine content of the locus ceruleus.45As
expected based on the DSP-4 experiments, bilateral
locus ceruleus lesions prior to a unilateral sensorimo-
tor cortex lesion results in poorer behavioral recover-
ies as compared to controls that had sham locus cer-
uleus lesions.46Again, the locus ceruleus lesions had
no effect on locomotion in rats that later had sham
Although predominately ipsilateral, each locus ce-
ruleus projects to both cerebral hemispheres,47,48and
unilateral left or right locus ceruleus lesions similarly
impair recovery after a subsequent right cortex le-
sion.46Locus ceruleus neurons project to the cerebral
cortex and subcortical structures via the dorsal norad-
renergic bundle (DNB), which can also be lesioned
permitting selective noradrenergic depletion of each
hemisphere.49Selective lesion of noradrenergic pro-
jection fibers to the cerebral cortex contralateral (but
not ipsilateral) to a subsequent sensorimotor cortex
lesion impairs the recovery of locomotor ability (FIG.
2).50Moreover, the norepinephrine content in the con-
tralateral but not ipsilateral cerebral cortex in rats with
contralateral DNB–sham DNB lesions correlates with
the rate of motor recovery.50These results are not only
consistent with the role of norepinephrine as a modu-
lator of post–brain injury recovery, but suggest that
the effect is mediated in the cerebral hemisphere con-
tralateral to the site of cortical injury.
H1H2 H3H4 H5H6
D2 D3D4D5D6 D7D8 D9
0. 1 mg/kg
FIG. 1. Effect of clozapine at different doses on locomotor recovery after unilateral sensorimotor cortex injury. Trials are identified in
hours (H) or days (D) after the first postoperative behavioral testing trial (zero hours, H0) in which the rat is required to traverse a narrow
horizontal beam. The baseline first trial, H0, was given 24 hours after cortex lesion surgery. A single dose of vehicle or drug was given
immediately after the baseline trial. Symbols represent locomotor scores for each trial (mean ? SEM). Motor performance was rated on
a seven-point scale by an observer blind to the study hypothesis: 1, the rat is unable to place the affected hindpaw on the horizontal
surface of the beam; 2, the rat places the affected hindpaw on the horizontal surface of the beam and maintains balance for at least 5
seconds; 3, the rat traverses the beam while dragging the affected hindpaw; 4, the rat traverses the beam and at least once places the
affected hindpaw on the horizontal surface of the beam; 5, the rat crosses the beam and places the affected hindlimb on the horizontal
surface of the beam to aid less than half its steps; 6, the rat uses the affected hindpaw to aid more than half its steps and; 7, the rat
traverses the beam with no more than two footslips. Rats given 1.0 or 10.0 mg/kg of clozapine of had poorer overall recoveries than
those given 0.1 or 0.5 mg/kg (ANOVA F4,51; p ? 0.014, Fisher’s LSD p ? 0.02, respectively). Clozapine had no effect on beam-walking
scores in sham cortex-lesioned rats at any dose (data not shown). Reproduced from Goldstein and Bullman, 2002.39
NEUROTRANSMITTERS AND MOTOR ACTIVITY453
NeuroRx?, Vol. 3, No. 4, 2006
Norepinephrine, experience, plasticity, and the
contralateral homotypic cortex
After several weeks, there is use-dependent in-
creased dendritic arborization in the homotypic cortex
contralateral to a lesion of the forelimb sensorimotor
esis,8,12,14,51–54with increases in layer V synapse-to-
neuron ratios and dendritic arborizations that can be
detected after approximately 30 days.12,14The en-
hanced dendritic arborization is use-dependent (i.e.,
there are complex interrelationships among the effects
of a brain lesion, behavioral experience, and neuro-
anatomical changes).54,55Neither a lesion nor asym-
metrical limb-use alone accounts for the increases in
contralateral layer V pyramidal neuron dendritic ar-
borizations.55These data are consistent with a rela-
tionship between recovery and norepinephrine content
of the contralateral cerebral cortex.
Interaction between pharmacological intervention
and experience or training in functional recovery
after focal brain injury
As already noted, neurotransmitter-mediated effects on
functional recovery after brain injury depend on the ani-
FIG. 2. Effects of prior left dorsal noradrenergic bundle (DNB) lesions on locomotor recovery after a subsequent right sensorimotor
cortex lesion. Behavioral testing was performed with the same paradigm as described for FIG. 1. Each animal’s recovery was calculated
from the area under the curve formed by graphing score against time. The left panel shows recovery for animals with either a left DNB
lesion (noradrenergically denervating the left cerebral hemisphere) or sham left DNB lesion prior to a right sensorimotor cortex lesion or
sham right sensorimotor cortex lesion (Error bars are ?/? SEM). Left DNB lesions had no effect on motor performance in rats with a
subsequent sham sensorimotor cortex lesion. Cortex-lesioned rats with prior left DNB lesions had significantly impaired recoveries
(areas under the time–effect curves) compared with cortex-lesioned rats with sham DNB lesions (ANOVA F3,16, p ? 0.001; left DNB
lesion-cortex lesion versus sham DNB lesion-cortex lesion, Fisher’s LSD, p ? 0.02). The right upper panel gives the correlation between
recovery and norepinephrine content in the left cerebral hemisphere and the right lower panel shows the lack of correlation between
recovery and norepinephrine content in the right cerebral hemisphere in these same animals. There was no effect of a right (ipsilateral)
DNB lesion on recovery (data not shown). The results suggest that norepinephrine exerts its influence on locomotor recovery, at least
in part, in the cerebral hemisphere contralateral to a sensorimotor cortex lesion. Modified from Goldstein and Bullman, 2002.50
LARRY B. GOLDSTEIN454
NeuroRx?, Vol. 3, No. 4, 2006
mal’s behavior. For example, with both amphetamine and
haloperidol effects on motor recovery in rats are blocked if
the animals are restrained rather than given motor practice
after drug administration.25A smaller effect of the drug is
found in rats that are allowed to ambulate freely but are not
given specific training, and more dramatic improvements of
recovery occur if training is used in combination with the
drug.10The effect of amphetamine on motor recovery in
cats with cortical injuries is also dependent on the animal’s
experience after lesioning.26Similarly, amphetamine-facil-
itated recovery of stereoscopic vision in visually decorti-
cated cats also depends on visual experience after the drug
Effect of norepinephrine on recovery: mechanism
The cellular mechanisms that underlie learning pro-
vide a useful paradigm for considering the possible
mechanism of norepinephrine-modulated recovery be-
cause the effect is experience dependent. Long-term po-
tentiation (LTP) is the best-understood putative cellular
mechanism of learning and memory.56,57In the hip-
pocampal formation, LTP is induced by a single, tran-
sient, high-frequency stimulation of excitatory neural in-
puts. Neurotransmitters such as catecholamines,58–61
GABA,62–64and acetylcholine65,66can affect LTP. Thus,
it is possible that norepinephrine could initially affect
LTP induction, which in turn could lead to the neuro-
anatomical changes discussed.
OTHER NEUROTRANSMITTERS AND MOTOR
Acetylcholine would be expected to facilitate the
induction of LTP by suppressing voltage-activated po-
tassium conductance.57Activation of the muscarinic
cholinergic receptor facilitates the induction of LTP in
the rat dentate gyrus.67Scopolamine, an anticholin-
ergic, interferes with motor recovery after cortex in-
farction in rats.68Giving acetylcholine has the oppo-
site effect, facilitating recovery in animal brain injury
models.69It is also possible, however, that the putative
effects of cholinergic drugs on recovery might be me-
diated by their indirect actions on noradrenergic neu-
GABA influences LTP and learning and memory.
Stimulation of inhibitory GABAergic inputs to the hip-
pocampal formation,63,72as well as indirect GABA ago-
nists such as benzodiazepines, suppress the induction of
LTP.73Intracortical infusion of the inhibitory neuro-
transmitter increases the hemiparesis produced by a
small motor cortex lesion in rats.74Diazepam, an indirect
GABA agonist, impedes recovery from the sensory
asymmetry caused by anterior-medial neocortex damage
in the rat.75Amphetamine administration influences the
activity of GABAergic neurons, leading to lower extra-
cellular GABA concentrations.76This would be expected
to enhance the induction of LTP.
More limited data are available concerning serotonin.
Fluoxetine combined with training did not alter the de-
gree or rate of recovery of function in rat, compared with
There are complex interrelationships among the levels
of certain central neurotransmitters, brain plasticity, be-
havioral experience, and recovery after brain injury. For
locomotor recovery after injury to the sensorimotor cor-
tex, extensive data indicate an important role for norepi-
nephrine. Understanding the neurobiological processes
underlying recovery, and how they might be manipu-
lated, may lead to novel strategies to improve stroke-
related gait impairments in humans.
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