Drug-induced rotation intensity in
unilateral dopamine-depleted rats is not
correlated with end point or qualitative
measures of forelimb or hindlimb motor
performance
G. A. Metz, and I. Q. Whishaw
Canadian Centre for Behavioural Neuroscience, University of
Lethbridge, 4401 University Drive, Lethbridge, AB, Canada T1K
3M4
Received 11 May 2001; revised 19 November 2001; accepted 11
December 2001. Available online 21 March 2002.
Abstract
The pharmacological induction of rotational (circling) behavior is
widely used to assess the effects of lesions to the dopaminergic
system and the success of treatment strategies in rat models of
Parkinson's disease. While the number of rotations under
apomorphine, L-DOPA and amphetamine is related to the extent of
dopamine depletion after unilateral 6-hydroxydopamine lesion of
the nigrostriatal dopamine system, the relationship of the intensity
of rotational behavior to the degree of impairment in motor
behavior is unclear. The present study examined this question by
correlating rotational behavior and motor abilities in a rat analogue
for Parkinson's disease produced by unilateral nigrostriatal bundle
lesion with 6-hydroxydopamine. Ipsiversive and contraversive
rotation was measured in the rats following systemic
administration of low and high doses of apomorphine, the
dopamine precursor L-DOPA, and amphetamine. The motor
assessment included end point and qualitative measures of foreand hindlimbs assessed in a skilled reaching task and a skilled
ladder rung walking task. The intensity of drug-induced rotation
did not correlate with the measures of motor performance.
We conclude that independence of rotational behavior and motor
performance argues that both the assessment of 6hydroxydopamine behavioral deficits and potential treatments for
the functional deficits require comprehensive assessment,
including both measures of rotation and motor behavior.
Author Keywords: amphetamine; apomorphine; L-DOPA; skilled
reaching; 6-hydroxydopamine; Parkinson's disease
Article Outline
Experimental procedures
Animals
Surgery
Skilled forelimb reaching apparatus
Skilled horizontal ladder rung walking apparatus
Video analysis
Rotation apparatus
Behavioral testing and analysis
Experimental design
Drug administration
Rotation tests
Reaching success ratings
Reaching movement rating scores
Skilled horizontal ladder rung walking task
Histology
Statistical analysis
Results
Histology
Rotation tests
Apomorphine
L-DOPA
Amphetamine
Reaching success and movement rating
Success
Rating
Skilled rung walking performance
Correlation analysis
Discussion
Conclusion and implications for the Parkinson animal model
Acknowledgements
References
In the most common rat analogue for Parkinson's disease,
dopaminergic fibers are destroyed by unilateral injections of the
neurotoxin 6-hydroxydopamine into striatum, substantia nigra or
its major efferent projection, the nigrostriatal bundle. The lesion
can result in almost complete unilateral dopamine depletion,
causing moderate to severe functional asymmetries. For instance,
rats with unilateral dopamine depletion show asymmetries in
spontaneous locomotion (Schwarting; Fornaguera and Miklyaeva)
and body posture ( Miklyaeva et al., 1997). Tests of sensorimotor
integration reveal impairments on the side contralateral to the
lesion ( Schallert; Schallert and Schallert). Additionally, rats with
unilateral 6-hydroxydopamine lesion demonstrate deficits in
skilled forelimb use in various reaching tasks ( Dunnett; Montoya;
Montoya; Miklyaeva; Whishaw; Whishaw and Whishaw).
Performance in skilled motor tasks and other tests monitoring
motor asymmetries has been reported to reflect the extent of
dopamine depletion ( Fornaguera and Barneoud).
Animals with unilateral dopamine lesions also rotate
spontaneously and in response to various drug treatments.
Rotational behavior is considered to represent a reliable
physiological measure of dopamine depletion and asymmetric
dopamine receptor stimulation. By applying dopamine agonists
such as apomorphine (Anden; Ungerstedt and Ungerstedt) or LDOPA ( Costall; Robertson and Robertson), dopamine receptors
are directly stimulated leading to rotation contraversive to the
dopamine-depleted hemisphere. In contrast, ipsiversive rotation is
induced by drugs, such as amphetamine, that enhance dopamine
release and block its uptake at the terminals in the intact
hemisphere (e.g. Lynch and Robinson).
Earlier studies describe the intensity of rotational behavior as a
graded outcome that is related to various physiological parameters.
Some studies suggest that the intensity of rotational behavior under
dopamine agonists reflects the degree of dopamine depletion (Hefti
et al., 1980), however, the relationship of rotational behavior and
receptor supersensitivity is controversial (e.g. Costall and
Staunton). Other studies suggest that rats with various lesion
severities can be selected based on rotation intensity ( Schmidt and
Schmidt). Several studies indicate that the intensity and direction
of this motor response under amphetamine reflect structural
reorganization processes ( Lynch and Carey, 1989), or facilitatory
influences of the mesolimbic dopamine system ( Kelly; Kelly;
Pycock; Ziegler and Robinson). Based on these various lines of
evidence, it is assumed that rotational behavior is related to the
behavioral deficits produced by dopamine depletion (e.g. Burbaud;
Schwarting and Schwarting). Consequently, rotational behavior is
used to assess both lesion size and therapeutic benefits of treatment
strategies (e.g. Bjorklund; Dunnett; Dunnett and Brown).
Although rotational behavior tests are widely used, no study has
demonstrated a correlation of the degree of rotation displayed by
rats with unilateral 6-hydroxydopamine lesions with other
impairments produced by dopamine depletion. Previous studies
indicate negative or non-linear relationships (Lee and Kirik). This
issue is important because if rotational behavior is related to other
functional deficits then it would be possible to use therapy-induced
changes in rotational screens to predict functional improvements.
The purpose of the present experiment is therefore to assess the
relationship between rotational behavior and fine motor function in
rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal
bundle. Rotational behavior was measured as the number of
contralateral rotations with low and high doses of apomorphine,
and low and high doses of L-DOPA. Ipsilateral rotations were
assessed after injection of amphetamine. These data were
correlated to performance in a skilled forelimb reaching task and a
skilled hindlimb ladder rung walking task.
Experimental procedures
Animals
Subjects were 14 adult female Long Evans rats (raised at the
University of Lethbridge vivarium) weighing 260–310 g at the
time of surgery. The rats were housed in groups of four to six
animals under a 12:12 h light/dark cycle, with lights on at 8 a.m.
Throughout the experimental period, the rats received water ad
libitum. For the skilled forelimb reaching task, the animals were
food-deprived 2 weeks before training or testing began. Each day,
the rats received supplemental food to maintain body weight at
95% of the initial body weight. When not tested in the reaching
task, the rats received food ad libitum. All animal experiments
were approved by the University of Lethbridge animal care
committee.
Surgery
Thirty minutes prior to surgery, the rats received 25 mg/kg i.p.
desmethylimipramine (Sigma Chemicals, St. Louis, MO, USA).
The rats were then anesthetized with 60 mg/kg of sodium
pentobarbital. The neurotoxic lesions of the nigrostriatal bundle
were performed with injections of 6-hydroxydopamine
hydrobromide (2 l of 4 mg/ml in 0.9% saline with 0.02% ascorbic
acid; Whishaw et al., 1986) at the following coordinates: 4.0 mm
posterior to bregma, 1.5 mm lateral to the midline, and 8.5 mm
ventral to the skull surface, with the skull flat between lambda and
bregma (according to coordinates by Paxinos and Watson, 1998).
Infusion took place over 5 min, with 5 min for diffusion.
Skilled forelimb reaching apparatus
All animals were trained and tested in a transparent Plexiglas box
(40¥45 cm and 13.1 cm wide) which was mounted on a floor of
paperboard. In the middle of the front wall, a 1-cm-wide, vertical
opening allowed the animals to reach for the pellets placed on a
shelf attached to the outside of the front wall (Whishaw et al.,
1986). The shelf was positioned 4 cm above the floor. Two small
indentations on the upper side of the shelf, each aligned with one
side of the slit, served as indentations for the food pellets. The
distance of the indentations to the front wall was 1.5 cm. This
setup biased a rat to use only the limb contralateral to the lesion to
reach and prevented the retrieval of pellets using the tongue (
Whishaw et al., 1997b).
Skilled horizontal ladder rung walking apparatus
The animals were trained to cross a 1-m-long runway with
irregularly spaced round metal bars (Metz et al., 2001a). The gaps
ranged from 0.5 to 5 cm and the same pattern of bar arrangement
was used for all rats. The variable spacing prevented the rats from
anticipating the location of the rungs.
Video analysis
During reaching sessions, rats were filmed from a frontal view
with a Sony Video 8 CCD-VII portable camera with a shutter
speed of 1/1000 s. The reaching box was illuminated by a one arm
cold light source (Nicon). The ladder walking performance was
video-recorded from a lateral perspective. The tapes were analyzed
frame-by-frame on a Sony Video 8 recorder.
Rotation apparatus
To measure spontaneous or drug-induced turning bias, the animals
were placed individually into 39 cm diameter round rotometer
bowls. A cuff was wrapped around the trunk of the rat, and this
was connected to a lead and swivel, which in turn was connected
to a computer. A custom-made computer program recorded the
turns in the direction ipsilateral and contralateral to the lesion in 5min time intervals.
Behavioral testing and analysis
Experimental design
The time course of manipulations and behavioral measurements is
illustrated in Fig. 1. Four weeks before surgery, all rats were
trained in the skilled forelimb reaching task. Baseline
measurements in reaching and rung walking performance were
collected the day before surgery was conducted. After surgery, the
animals were continuously trained in the reaching task starting 5
days after surgery. Behavioral testing was performed at time points
at which stable pathological conditions can be expected (Lynch;
Fornaguera and Miklyaeva). Rotation tests were performed
between 5 days and 150 days after surgery, with at least 1–2 weeks
between tests. Postoperative reaching and rung walking
performance were recorded at 2 months after lesion.
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Fig. 1. Time chart summarizing the order of the manipulations and behavioral
tests. Pretraining, training and testing sessions included skilled forelimb reaching
and skilled walking tests. Rotation and reaching performance were assessed at
chronic time points after the nigrostriatal lesion. Sp., spontaneous rotation.
Drug administration
Apomorphine-hydrochloride (0.01 mg/kg low dose and 0.05 mg/kg
high dose) was dissolved in 0.9% saline solution with 0.2%
ascorbic acid and injected s.c. L-DOPA (4 mg/kg low dose and 8
mg/kg high dose) and benserazide (12.5 mg/kg) were also
dissolved in saline–ascorbic acid solution and injected i.p. LDOPA was injected 30 min after i.p. administration of the
peripheral DOPA decarboxylase inhibitor benserazide. Amphetamine (5 mg/kg) was dissolved in 0.9% saline solution and
injected i.p. All drugs were obtained from Sigma.
Rotation tests
Measurements of rotational behavior were based on the method
described by Ungerstedt (1971). For monitoring spontaneous
rotation, animals did not receive any drug treatment and were
tested for a 60-min interval in rotation bowls. In the drug-testing
sessions, the rats were injected either with apomorphine, L-DOPA
or amphetamine. Animals were then placed individually in the
rotation bowls. Rotations were counted for 40 min after
apomorphine, for 150 min after L-DOPA and for 270 min after
amphetamine. Rotation intensity under apomorphine and L-DOPA
used for correlation analysis was the total number of rotations
during recording intervals. Data for spontaneous rotation and
rotation after amphetamine treatment are presented as net rotation:
Net ROTATION=number of contralateral rotations-number of
ipsilateral rotations
For further analysis, the animals were subdivided into groups of
low and high rotation according to their number of rotations after
administration of 0.05 mg/kg apomorphine 14 days after the lesion.
Low rotation was defined as six or less rotations per minute during
the first 40 min after drug administration, and high rotators were
defined as seven or more rotations per minute (Schwarting and
Huston, 1996).
Reaching success ratings
Success ratings were used as an indicator of the animals' accuracy
in reaching performance. A `miss' was recorded if an animal
touched and missed the pellet or if it needed more than one attempt
to grasp it. An attempt was defined as a forelimb movement
towards the pellet. Additionally, if the animal lost the pellet in the
cage after grasping, a miss was scored. Every pellet that was
grasped on the first attempt and put into the mouth was counted as
a `success'. The results are presented as reaching success:
Reaching SUCCESS=number of successful reaches/number of
pellets given (20)¥100
All animals were trained preoperatively in the reaching paradigm
until a stable performance over 5 consecutive days was obtained.
The success rate presented in this study was based on the ratings
made from the video recordings obtained in the postoperative
testing session.
Reaching movement rating scores
The qualitative ratings of the reaching movements were performed
from the video tapes by frame-by-frame analysis (Metz and
Whishaw, 2000). This rating scale is derived from an Eshkol–
Wachman movement notation ( Eshkol and Wachman, 1958) of
skilled reaching (Pellis and Whishaw, 1990) which allows to
analyze the relations and changes of relations between parts of the
body and limbs. The following movement components of the
reaching movement were analyzed from a frontal point of view: (1)
Orient: the head is oriented towards the target and the snout is
inserted through the slot to sniff. (2) Limb lift: the mass of body
weight is shifted to the hindlimbs, the hindlimbs are aligned with
the body and parallel to each other (indicating normal base of
support). The forelimb is lifted so that the digits are aligned to the
midline of the body. (3) Digits close: the palm is partially
supinated and approaches the midline of the body, the digits are
semiflexed. (4) Aim: the elbow comes in to the body with a
shoulder movement while the digits retain their position on the
midline of the body. (5) Advance: the elbow is positioned in a
narrow angle to the body, the forelimb moves forward and is
directed to the target. The head and the upper body raise and the
weight is shifted to the front. This movement is accompanied by a
moderate lateral body movement towards the reaching limb. (6)
Digits open: the digits are opened with parallel discrete limb
movement, the palm is not fully pronated. (7) Pronation: the elbow
adducts and pronates over the target in an arpeggio movement. (8)
Grasp: the arm remains still, while the digits close and then the
paw is lifted holding the food pellet. (9) Supination I: the elbow is
adducted, and the palm is supinated to approximately 90°. (10)
Supination II: the head drops to the level of the paws, and the rat
sits back on the haunches. The palm is supinated to present the
food pellet to the mouth. (11) Release: the food pellet is released
into the mouth by opening the digits.
For each of the 11 movement components, a score of 0 was given
when this movement component was completely absent, a score of
0.5 was given if the movement was present but abnormal, and one
point was given if the movement was normal (Metz and Whishaw,
2000). To enhance resolution for correlation analysis, each of the
individual subcomponents was also rated using this scale.
Skilled horizontal ladder rung walking task
Deficits in limb coordination and limb placing were examined by
assessing the rat's ability to navigate across a runway with
irregularly spaced rungs. Crossing the runway required that
animals accurately place their fore- and hindlimbs on the bars. In
baseline and the postoperative testing sessions, all animals were
trained over five trials to cross the beam. On the following day, the
rats were tested in three trials and their performance was videorecorded. From these tapes, the number of steps and the number of
foot faults (errors) for each hindlimb were counted. Three trials
were averaged to calculate an error ratio (errors/step) for each
hindlimb. The following rating system was used: 0 point was given
when no placing error occurred, one point was given if a rat
corrected foot placement as the foot touched the bar, two points
were given if a rat placed a foot onto a bar, withdrew it and then
replaced it, three points were given for a foot slip after the food
was placed on a bar, and four points were given when a paw
completely missed a rung.
Histology
After behavioral tests were finished, animals were deeply
anesthetized and perfused through the heart with a 0.9% sodium
chloride solution and picric acid (Lana's fix). The brains were
removed and postfixed for 14 days. The brains were cut in 50-m
sections on a vibratome and mounted on gelatin-coated slides. For
tyrosine hydroxylase (TH) immunocytochemistry, the sections
were washed in 1 M phosphate buffer and then incubated overnight
at room temperature with anti-TH monoclonal antiserum (1:10000,
Sigma). The sections then were processed by the ABC method
(Vector, Vectastain, Burlingame, CA, USA) with anti-mouse
antiserum IgG and horse serum and reacted with 3,3'diaminobenzidine tetrahydrochloride (0.06%), hydrogen peroxide
(0.03%) and nickel solution. Some sections were processed to
control for either monoclonal antiserum or antibody stain.
For quantification of mesencephalic dopamine depletion, the three
separate sections through the mesencephalon were chosen which
showed the highest TH-positive cell density in the intact
hemisphere. All analyzed sections were located between 4.8 and
5.8 mm posterior to bregma. The number of TH-positive cell
bodies was counted; (1) in the area medial to the ventral tegmental
area (here referred to as medial tegmental areas), (2) in the ventral
tegmental area, (3) in the substantia nigra pars compacta, and (4) in
the lateral substantia nigra (according to Paxinos and Watson,
1998). The cell number of each quadrant in three mesencephalic
sections was averaged. A TH-positive cell was defined as a
densely stained cell body visible on the respective section ( Fig. 2).
To correct for variable staining intensity, the cell number was
analyzed as a ratio of the cell number in the lesion area versus the
cell number in the contralateral hemisphere. The histological data
were compared between the groups of low and high rotators based
on the rotation intensity.
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Fig. 2. Photomicrograph of a cross section through the ventral mesencephalon of a
representative unilateral 6-hydroxydopamine lesion rat with absence of TH
immunoreactive cells in the ipsilateral substantia nigra (arrows). Insets represent
cell density in the ventral tegmental area. MTA, medial tegmental areas; VTA,
ventral tegmental area; SNc, substantia nigra pars compacta; SNl, substantia nigra
lateral portion. Magnification: 250¥, 400¥ (inserts).
Statistical analysis
Statistical analysis was performed using a Statview software
package (Abacus Concepts, CA, USA, 1996). The data are
presented in bivariate plots displaying the relationship between two
variables. Regression lines and Pearson's correlation coefficients
were calculated. Spearman's rank correlation coefficients were
computed for paired comparisons using ordinal data. For other
data, Fisher's R to Z transformation and a `z-test' were applied to
calculate the significance of the correlation coefficients. Repeated
measurements were analyzed with one-way analysis of variance
(ANOVA). Differences in between-group comparisons were
assessed with unpaired t-tests and within-subject comparisons were
performed using paired t-tests. A P value of less than 0.05 was
chosen as the significance level for all statistical analyses.
Results
Histology
TH immunostaining indicated that the nigrostriatal 6hydroxydopamine injection reduced the number of dopaminergic
cells and fibers. Figure 2 illustrates a section through the
mesencephalon of a lesion animal with representative lesion
extent. The lesion resulted in an almost complete unilateral loss of
nigrostriatal fibers and retrograde axonal degeneration leading to
absence of TH-positive fibers in substantia nigra dorsal and ventral
tier and the lateral portion of nigral neurons. As a consequence,
nigral dopaminergic cell bodies and striatal dopaminergic
terminals were reduced, but some were spared in the ventral
tegmental area.
The cell count analysis revealed a significant reduction of THpositive cells in the lesion mesencephalon in all areas compared to
the intact hemisphere. The mean number of cells in the lesion
hemisphere was 55 in low rotators and 50 in high rotators, in the
non-lesion hemisphere it was 289 in low rotators and 242 in high
rotators. The mean loss of TH-positive cells was 80%, with 80.9%
in low rotators and 79.4% in high rotators. Figure 3 illustrates that
the substantia nigra pars compacta and the lateral portion of the
substantia nigra were most affected by the neurotoxic lesion, while
medial tegmental areas showed the lowest degree of cell loss (all P
values <0.001). Also, the number of cells in the ventral tegmental
area was significantly reduced in the lesioned hemisphere
(F(1,13)=81.8, P<0.001). Among the medial tegmental areas, the
ventral tegmental area and substantia nigra pars compacta, there
was no difference between low and high rotating animals. In the
lateral portion of substantia nigra neurons, however, low rotators
showed some remaining intact cell bodies whereas high rotators
showed complete absence of TH-positive cells (P>0.05).
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Fig. 3. Mean number of TH-positive cells in the lesion versus the non-lesion side
in low and high rotating animals. Cells were counted in the medial tegmental
areas, ventral tegmental area, and substantia nigra pars compacta and its lateral
portion. Note that the lateral portion of the substantia nigra is present only in low
rotating animals. The data are presented as group means±S.E.M. (n=14 with three
sections each).
Rotation tests
Apomorphine
The rotation under the high dose of apomorphine, 0.05 mg/kg,
elicited rotational behavior to the side contralateral to the lesion in
all animals (Fig. 4). The rotation response in low rotators (n=5)
remained unchanged 14 days after lesion as compared to the 5-day
session. In contrast, the response of high rotators (n=9) increased
four-fold from 5 days after lesion to 2 weeks after lesion (t(13)=7.53, P<0.001).
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Fig. 4. Rotation response in a 40-min interval under a high dose (0.05 mg/kg) of
apomorphine on days 5 and 14 after 6-hydroxydopamine lesion. Rotation intensity
was not different between the two testing sessions in low rotators, but increased in
high rotators. Data presented as group means±S.E.M. Asterisks indicate
significance levels: ***P<0.001, paired t-test (n=5 low rotators, n=9 high
rotators).
In a 60-min test for spontaneous rotation, animals revealed no
major asymmetries in turning behavior (Fig. 5A). In contrast,
apomorphine-induced contraversive rotation (Fig. 5B) started
immediately after injection with a maximum number of rotations
occurring between 10 and 15 min after drug administration. The
rotation intensity under high apomorphine was significantly
enhanced as compared to the low dose or the net rotation during
the control session (P values <0.05; see Fig. 5A, B). The course of
rotation intensity under both apomorphine doses in each session
showed a significant interaction with time (low apomorphine
F(7,91)=3.44, P<0.01; high apomorphine on 14 days
F(7,91)=4.79, P<0.001; ANOVA).
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Fig. 5. Time courses of rotation intensity in 5-min time bins in 6hydroxydopamine lesion rats. (A) Spontaneous rotation, (B) after low (0.01
mg/kg) and high (0.05 mg/kg) doses of apomorphine, (C) after low (4 mg/kg) and
high (8 mg/kg) doses of L-DOPA, and (D) after 5 mg/kg amphetamine. Note that
rotation intensity correlated with the dose of drug treatment. Data for low and high
rotators were combined and are presented as group means±S.E.M. (n=14).
L-DOPA
The contraversive rotation intensity after the high dose of L-DOPA
(8 mg/kg) was significantly increased as compared to the low dose
(4 mg/kg) or the control session (P values <0.05; see Fig. 5C). The
rotation intensity showed a significant interaction with time (low
L-DOPA F(29,377)=2.59, P<0.001; high L-DOPA
F(29,377)=4.44, P<0.001). The peak of L-DOPA action in the
rotation response was observed 30 min after injection, and the drug
effect lasted for up to 125 min after the application.
Amphetamine
The ipsiversive rotation response under amphetamine finally lasted
for more than 4 h with a peak of action at 15 min after
administration (Fig. 5D). The repeated measurements of the
rotation intensity revealed a significant interaction with time
(F(53,689)=12.66, P<0.001).
Reaching success and movement rating
Success
Preoperatively, the rats obtained an average of 48% of the pellets.
After the 6-hydroxydopamine lesion, animals showed a mean
reaching success of approximately 18% and no changes in
performance throughout the postoperative test period (P>0.05).
After the lesion, the animals needed more attempts to obtain a
pellet, and often they dropped the food in the cage without eating
it. There was no significant difference in reaching performance
between low and high rotating animals.
Rating
Scoring of reaching movements in the lesion animals revealed
impairments in a subset of the movement components as compared
to preoperative values (baseline mean score 0.96, Fig. 6). The
orient, digits close, and digits open movement components were
not affected by the 6-hydroxydopamine lesion. In contrast, limb
lift, aim, advance, pronation, grasp, supination I and II and release
were significantly impaired after lesion as compared to
preoperative values (all P values <0.001). The impairments in the
groups of low and high rotators did not differ.
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Fig. 6. The qualitative reaching movement ratings for 11 movement components
in rats with 6-hydroxydopamine lesions. Lower scores reflect impairments of the
respective movement component. Note that there was no difference between low
and high rotators. Data presented as group means±S.E.M. Asterisks indicate
significance levels: ***P<0.001, unpaired t-test compared to the maximum score
of 1 (low rotators n=5, high rotators n=9).
The deficits in the reaching movements were marked by
difficulties in adducting the elbow and bringing the paw into the
midline. This resulted in loss of precise aiming and required the
substitution of whole body movements to manipulate the limb
toward the food. Pronation was impaired due to incomplete or
absent arpeggio movements, so that the paw was not directed to the
target and the area of the target was not palpated. When the food
pellet was successfully grasped, the paw was dragged on the shelf
without supination. The paw was also not supinated to present the
food to the mouth and so the unaffected paw was used to grasp and
assist the affected paw. Finally, food pellet release was abnormal
as the digits could not open completely to release the pellet. Other
postural adjustments necessary to maintain reaching success were
also modified. For instance, weight support was no longer in a
diagonal fashion on the contralateral forelimb and ipsilateral
hindlimb, but shifted to the unimpaired side. Reaches frequently
fell short of the target in part due to the rats' inability to shift the
body forward as the paw was advanced.
Skilled rung walking performance
After preoperative baseline training, all rats crossed the whole
length of the ladder beam with one or less errors of fore- or
hindlimbs (resulting in a ratio of less than 0.08 errors per step).
This performance was significantly impaired after lesion as rats
showed a mean of 0.3 forelimb errors and 0.13 hindlimb errors per
step when averaged for contra- and ipsilateral side (all P values
<0.01). Impairments among low and high rotators were similar.
The number of errors made with contralateral fore- and hindlimbs
was not significantly different from those of the ipsilateral side
reflecting disturbed inter-limb coordination (see Fig. 7A, B).
Whereas the animals preoperatively showed no foot fall errors
(error score 0 on five-category scale), these errors occurred
frequently after the lesion, resulting in a mean score of 2.6 points
for forelimbs and 3.1 points for hindlimbs (all P values <0.01; Fig.
6C, D). The scores of contralateral hindlimbs were only different
from the ipsilateral side in forelimbs (t(13)=5.03, P<0.01). Across
low and high rotators, there was no significant difference in the
number of errors made and error scores achieved.
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Fig. 7. Skilled rung walking performance in groups of low and high rotating
animals. (A) Number of forelimb and (B) hindlimb errors per step, and (C) error
score for forelimbs and (D) for hindlimbs for ipsi- and contralateral limbs. The
bold line indicates preoperative baseline values. A lower error rate per step
indicates better limb placing accuracy. A lower score reflects a better ability to
correct for the error. This task assesses inter-limb coordination and therefore
impairs both ipsi- and contralateral limb placement accuracy. The groups of low
and high rotating animals were not different from each other. Data presented as
group means±S.E.M. Asterisks indicate significances: *P<0.05, unpaired t-test
between ipsi- and contralateral limbs (n=5 low rotators, n=9 high rotators).
Correlation analysis
Performance in the reaching task and the ladder rung walking task
did not reveal a significant relationship. Correlations between
rotation intensities produced by different drugs and doses revealed
significant correlations between apomorphine-induced rotations
and L-DOPA-induced rotations (Table 1). No other correlations
were significant.
Table 1. Correlation coefficients of drug-induced circling intensity
(<1K)
Correlation coefficients (r values) for the comparison of the circling response to
different drug treatments. Significance levels are given for the correlation
coefficients are indicated by asterisks: *P0.05; **P0.01; ***P0.001.
Correlations between net rotation and the measures of performance
in the motor tests gave only one significant correlation, reaching
success and amphetamine rotation (Table 2). Despite the lack of
significant correlations between the drug-induced measures and the
motor measures, there were trends, but as many of the trends were
positive as were negative (Fig. 8). This indicates that different
measures of behavior did not reflect the results obtained in druginduced rotation.
Table 2. Correlation coefficients of circling intensity and behavioral measures
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Correlation coefficients (r values) for the comparison of the circling response to
different drug treatments. FL, forelimb; HL, hindlimb. Significance levels for the
correlation coefficients are indicated by asterisks: *P0.05; **P0.01; ***P0.001.
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Fig. 8. Correlations between reaching performance and rotation intensity (success
rate, left column, and reaching movement score, right column; n=14). (A) and (B)
low and high dose of apomorphine, (C) and (D) low and high dose of L-DOPA,
(E) and (F) amphetamine. Reaching success was positively related to rotation
intensity, whereas qualitative reaching performance showed a negative correlation.
Discussion
The present study investigated the relationship between druginduced rotation rates and the scores on two tests of motor
behavior in rats with a unilateral 6-hydroxydopamine nigrostriatal
bundle lesion. Administration of dopaminergic agonists resulted in
contraversive rotation, and amphetamine administration caused
ipsiversive rotation in all animals. Performance in skilled reaches
and in a ladder rung walking task revealed end point and
qualitative impairments in movements. Correlational analysis of
rotation intensity with the motor outcome showed no relation
between any of the three drug effects and motor performance in the
tasks. In addition, the scores in the motor tasks were not correlated.
These results suggest that rotational behavior and skilled
movement should be considered to be independent effects of 6hydroxydopamine depletions requiring conjoint measures to fully
assess loss and recovery of function.
Motor impairments and rotational behavior are the two most
commonly used measures of dopamine depletion in rodents (Hefti;
Whishaw and Whishaw). Hefti et al. (1980) showed that high
rotational intensity under apomorphine or L-DOPA can be
observed when more than 90% of striatal terminals are lost. In
contrast to these postsynaptically active drugs, rotation under the
presynaptically active amphetamine seems to be more sensitive in
animals with less severe dopamine depletion, as animals begin to
rotate after a 50% dopamine depletion ( Hefti et al., 1980). This is
in line with descriptions that rotation intensity under apomorphine
and amphetamine both produce independent results and are not
related to each other ( Casas and Becker). These data and the
observation that most changes in rotational behavior and motor
function occur within the first 2 weeks after lesion ( Marshall;
Neve; Pritzel; Schwarting and Schwarting) are in accordance with
the present findings.
The motor tasks of skilled forelimb reaching used in the present
study have also become standard for functional assessment of
dopamine depletions in rats (Whishaw; Whishaw; Miklyaeva;
Miklyaeva and Montoya). The present findings of impaired end
point and qualitative forelimb and hindlimb skill following
dopamine depletions are consistent with previous descriptions (
Whishaw; Whishaw; Whishaw; Montoya; Montoya; Miklyaeva
and Metz).
The present study describes two approaches to characterize the
relationship between rotational behavior and skilled motor
function. In the first, the animals were subdivided into groups of
low and high rotators and the respective motor function of the two
groups was analyzed separately. This comparison showed that,
although these groups developed distinctive and stable rotation
intensity within 2 weeks after the neurotoxic lesion, the motor
performance of both groups did not differ from each other. The
second analysis used correlations between rotation and movement
performance in individual animals, and this analysis also did not
reveal a significant relationship. The results of both comparisons
suggest that the rotational and motor measurements are
independent. This finding is consistent with previous reports,
Whishaw et al. (1986) and Lee et al. (1996), using a 6hydroxydopamine-induced dopamine depletion, and Loscher et al.
(1996), using gene-manipulated, spontaneously rotating rats,
indicating that motor impairments and rotation intensity are not, or
only weakly, related.
One possible explanation for the poor correlation between turning
bias and motor skill relates to individual variability in lesion
location. A minor variation in cannula placement might result in
damage to fibers that are differentially involved in rotation versus
skilled movements. This might suggest a somatotopy of the
nigrostriatal bundle in which the whole body movements used in
rotation, forelimb movements used for reaching, and forelimb and
hindlimb movements used for walking are partially independent.
This suggestion is supported by the observation that low rotators
showed a small number of residual intact dopaminergic cells in the
lateral part of the substantia nigra, while none of the high rotators
showed remaining cell bodies in this area. A few residual fibers
spared by a neurotoxic lesion could compensate for dopamine loss
and account for enhanced residual motor function (Robinson and
Song).
Another explanation for the present results could be provided by
individually different degrees of behavioral compensation
displayed by the animals in response to the lesion-induced deficits.
Skilled reaching movements have been described as being action
patterns (Metz and Whishaw). To continue performing successful
reaching movements after damage to the neural circuitry that
supports the movements, the animals have to make compensatory
adjustments. Since these movements are largely learned, and also
different from the original reaching movement pattern,
considerable individual variability may occur in the way that
animals learn to compensate.
A third explanation for the absent relationship between rotational
behavior and skilled motor function is based on individual neural
anatomy. A lesion, even when placed exactly at the same
anatomical site in different animals, could lead to different
anatomical disruptions due to slight innate variability in the neural
circuits. As a consequence, a lesion diversely disrupts the neural
circuit and also might trigger different responses to the damage
based on the individual differences in immune system constitution,
in neuronal response to injury, and in response to stress. Individual
differences in these allied systems are well-documented
(Mittleman; Mittleman and Piazza). Similar suggestions have been
made in other studies that have attempted to account for individual
differences in abilities following brain injury ( Castaneda;
Przedborski and Finkelstein).
Conclusion and implications for the Parkinson animal
model
The present results show that the intensity of rotational behavior in
the unilateral 6-hydroxydopamine rat model of Parkinson's disease
is a poor predictor of the impairment of motor function. The results
also show that the deficits in different kinds of motor function are
also not correlated. These results are unlikely to be an artifact of
the present study as a similar lack of correlation has been noted in
other studies that were not specifically directed toward the
question of relationships between symptoms. These results imply
that treatments which reduce rotation intensity will not necessarily
lead to parallel improvement in skilled motor function. Therefore,
a complete analysis of unilateral 6-hydroxydopamine lesioninduced deficits requires a combination of rotational and motor
tests. The outcome of such a testing battery should provide
comprehensive information about functional abilities in these
animals in basic and preclinical research.
Acknowledgements
This research was supported by grants from the Medical Research
Council and the Natural Sciences and Engineering Research
Council of Canada. G.A.M. was supported by grants from the
German Academic Exchange Service and the Alberta Heritage
Foundation for Medical Research.
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Corresponding author. Tel.: +1-403-329-24-08; fax: +1-403-32925-55; email: gerlinde.metz@uleth.ca