European Journal of Neuroscience, Vol. 15, pp.

2053±2056, 2002 ã Federation of European Neuroscience Societies

SHORT COMMUNICATION
Dopamine transporter knock-out mice are hypersensitive
to 3-nitropropionic acid-induced striatal damage

Pierre-O. Fernagut, Elsa Diguet, Mohamed Jaber,1 Bernard Bioulac and FrancËois Tison
Laboratoire de Neurophysiologie, UMR-CNRS 5543. 146, rue LeÂo Saignat, Universite Victor Segalen Bordeaux2, 33076
Bordeaux Cedex France
1
Psychobiologie des comportements adaptatifs, INSERM U259, Domaine de Carreire, rue Camille St SaeÈns, 33077 Bordeaux
Cedex France

Keywords: dopamine transporter, excitotoxicity, motor behaviour, nigrostriatal pathway

Abstract
Evidence suggests that dopamine is involved in the modulation of striatal excitotoxic processes. To further investigate this issue,
we studied the effects of systemic `low-dose' (total dose, 340 mg/kg in 7 days) 3-nitropropionic acid (3-NP) intoxication in
dopamine transporter knock-out mice (DAT±/±) compared to wildtype (DAT+/+) mice. Systemic `low-dose' 3-NP induced a
signi®cant impairment in a rotarod task only in DAT±/± mice. Histopathology also demonstrated a signi®cant reduction of the
striatal volume (±7%, P < 0.05), neuronal density (±12.5%, P < 0.001) and absolute number estimates of striatal neurons
(±11.5%, P < 0.001) in DAT±/± compared to DAT+/+ mice, with increased glial activation, independent of the degree of succinate
dehydrogenase inhibition. These ®ndings strengthen the hypothesis for dopamine modulation of excitotoxicity within the
nigrostriatal system.

Introduction
There is increasing evidence that dopamine exerts a permissive action
on striatal excitoxic processes (Jakel & Maragos, 2000). On one hand,
there exists a protective effect, of nigrostriatal dopaminergic trans-
mission disruption, upon striatal excitotoxic damage produced either
by malonate, kainic, quinolinic or 3-nitropropionic (3-NP) acids
(Jakel & Maragos, 2000). On the other hand, increased dopaminergic
transmission by methamphetamine enhances the striatal toxicity of
3-NP, an irreversible inhibitor of succinate dehydrogenase (SDH)
(Reynolds et al., 1998; Brouillet et al., 1999). Very recent develop-
ments suggest that this effect may be due to a regulatory function of
striatal dopamine on glutamate-related NMDA excitotoxicity
(Calabresi et al., 2001). These observations are of clinical relevance
regarding the role of endogenous dopamine or dopaminergic drugs on
the neurodegenerative process in diseases affecting the striatum, such
as Huntington's disease (HD) and striatonigral degeneration (SND)
(Tison et al., 1995; Jakel & Maragos, 2000; Waldner et al., 2001) or
striatal dysfunction in methamphetamine and cocaine abusers (Ernst
et al., 2000; Volkow et al., 2001). Here, we provide new evidence
suggesting that constitutive elevated striatal dopamine tone, as found
in dopamine transporter knock-out mice (DAT±/±), enhances the
histopathological and behavioural consequences of subacute low-
dose 3-NP intoxication.
Materials and methods
Animals
Experiments were performed on 18 adult homozygous DAT±/±
(n = 6) and wildtype (DAT+/+, n = 12) transgenic mice aged
6 months for a preliminary exploratory `high-dose' 3-NP experiment,
then in 12 DAT±/± and 12 DAT+/+ mice in a 3-NP `low-dose'
intoxication paradigm. Sixteen additional mice (8 DAT±/± and 8
DAT+/+) were used to assess the degree of 3-NP induced SDH
inhibition. Ten additional DAT+/+ mice, aged 6 weeks with the same
femur size as adult DAT±/± mice, were used as controls for a possible
size-effect bias (Bosse et al., 1997). Mice were obtained as described
previously (Giros et al., 1996). Genotypes were determined by
Southern blot analysis and phenotypes by lack of habituation to
novelty (Giros et al., 1996). Experiments were conducted according
to EEC recommendations (86/509) for animal care and use.
Rotarod
Animals were placed on a stationary rod (diameter, 70 mm) and were
trained to stay on it as it rotated at 5 r.p.m. Usually 4±6 training
sessions of 10 trials on consecutive days were needed to achieve the
maximal performance established at 180 s (Rondi-Reig et al., 1999).
The variable studied, 5 days after the last 3-NP injection, was the
mean time spent on the rod for each trial during a 10-trial session.

Correspondence: Professor F. Tison, as above.
E-mail: ftison@neuro.u-bordeaux2.fr
Received 19 November 2001, revised 30 March 2002, accepted 29 April 2002
3-NP intoxication
The concentration of 3-NP (Sigma, France), diluted in 0.1 M PBS
(pH = 7.4) was calculated to keep the injected volume (200 mL, using
a 500-mL Hamilton microsyringe) stable as doses increased. Mice
received 3-NP in two (12 h apart) i.p. daily injections. In a ®rst

doi:10.1046/j.1460-9568.2002.02047.x
2054 P.-O. Fernagut, et al.
exploratory experiment, a `high-dose' regimen was used (10 mg/
kg 3 4, 20 mg/kg 3 4, 30 mg 3 4, 50 mg/kg 3 4, then
8 3 60 mg/kg, total cumulated dose: 920 mg/kg in 12 days). Due
to high mortality in DAT±/± mice during intoxication, the following
`low-dose' regimen schedule was used: 10 mg/kg 3 4, 20 mg/
kg 3 4, 30 mg 3 4, then 2 3 50 mg/kg (total cumulated dose
340 mg/kg in 7 days). Mice were divided into four groups: DAT+/+
(PBS), DAT+/+(3-NP), DAT±/±(PBS), DAT±/±(3-NP). Control mice
received the same volume of PBS every 12 h.
Histological preparations and cell counts
Animals were perfused under pentobarbital overdose (50 mg/kg)
12 days postintoxication with 4% paraformaldehyde (PFA), pH = 7.4,
and brains were frozen in isopentane at ±40 °C. Couples of adjacent
10 mm-thick cryostat sections were collected throughout the striatum
every 100 mm for striatal surface and volume estimations (cresyl violet
staining). The extent of substantia pars compacta (SNc) cell loss was
estimated on adjacent 20 mm free ¯oating tyrosine hydroxylase- (TH-)
stained sections at the mid-nigral level (bregma, ±3.16 mm), as
described previously (Fernagut et al., 2002a). All positive neurons
lying outside a vertical line passing through the accessory optical tract
were counted on each side and on three adjacent sections. The
estimated number of neurons were those seen in a `pick' reference
section and not in an adjacent 20 mm `look-up' section (Coggeshall,
1992). The ®nal estimation of the number of neuronal pro®les per
animal was the mean of neurons sampled in both sides of the section
and on three different couples of adjacent sections. For striatal surface
analysis, four anatomical levels of the striatum were de®ned from
rostral to caudal (level 1, bregma +1.18 mm; 2, +0.98 mm; 3,
+0.26 mm; 4, ±0.22 mm), according to the mouse brain atlas of
Franklin & Paxinos (1997). The outer border of the striatum was
de®ned by the lateral ventricle medially, the corpus callosum dorsally
and laterally by a line drawn between the two anterior commissures.
Anatomical landmarks [aspect, size and situation of the anterior
commissures, corpus callosum, septum, lateral ventricles, striatum,
nucleus accumbens (NAc) and pallidum] were used to ensure that
levels studied were similar within and between groups. The estimated
striatal surface was the mean on each side of two adjacent 10-mm-
thick, randomly selected sections within the anatomical levels
considered. Additionally, the total volume of the striatum was
calculated according to the principle of Cavalieri (volume =
s1d1 + s2d2¼ + sndn, where s = surface area and d = distance
between two sections). Neuronal pro®les were then counted on striatal
sections selected randomly at the mid-striatal level 2 (bregma,
+0.98 mm) in four 0.2 mm2 cell counting areas (3 20 objective)
placed randomly within the striatum. Additionally, one 0.2 mm2 cell
counting area was placed as a control in the NAc just above the anterior
commissure. The estimated neuronal numerical density (Nv) was the
mean count of `tops' pro®les entirely within the counting area on two
couples of 10-mm-thick adjacent sections, in the determined dissector
volume (Vdis) (Nv = S`tops'/SVdis; Vdis = area 3 section height).
The estimated absolute number of neurons (N) per striatal section and
per animal was the mean numerical density in each striatum according
to the whole striatal section volume (Vref) (N = Nv 3 Vdis).
Glial ®brillary acid protein (GFAP) immunohistochemistry
(DAKO, rabbit anti-GFAP, 1 : 400, overnight, 4 °C) was performed
as described previously (Ghorayeb et al., 2001) at the mid-striatal
level 2. All positive cells within the entire striatum were counted.
Surface, volume and cell counts were performed by an investigator,
blind to the mouse treatment and genotype, using computer-assisted
image analysis (Biocom, Visioscan, Les Ullis, France). Femur size
was measured in all mice ex-vivo.
ã 2002 Federation of European Neuroscience Societies, European Journal of Neuroscience, 15, 2053±2056
Succinate dehydrogenase (SDH) histochemistry
3-NP-induced SDH inhibition was assessed according to Brouillet
et al. (1998). Eight DAT+/+ and 8 DAT±/± mice received either a PBS
or a 3-NP (50 mg/kg) injection (n = 4 each) and were killed 2 h later
± a delay suf®cient to observe a stable inhibition of SDH (Brouillet
et al., 1998). Brie¯y, 20-mm-thick sections collected throughout the
striatum were ®rst incubated (10 min) in 0.1 M PBS (37 °C), then
washed in PBS and immersed in the reaction medium [0.3 mM
nitroblue tetrazolinium (Sigma, France), 0.05 mM succinic acid
(Sigma, France) in 0.05 M phosphate buffer at 37 °C] for 30 min.
To determine nonspeci®c staining, adjacent sections were incubated
in the same reaction medium without succinic acid. After incubation,
sections were post®xed (10 min) in 2% PFA and washed in deionized
water. Mean SDH activity was determined as optical densities by
subtracting nonspeci®c staining from total staining by using an image
analysis system (Biocom, Densirag v2.0, Les Ullis, France).
Data analysis
All data are expressed as mean value 6 SEM. Statistical analysis was
performed using one-way ANOVA (with repeated measures when
appropriate) with the post hoc Scheffe test for multiple comparisons.
Results
During the exploratory 3-NP `high-dose' intoxication, all DAT±/±
mice died compared to 2/12 DAT+/+ mice. Using the `low-dose'
schedule, 1/6 DAT±/± mice died but none of the DAT+/+ mice. Thus,
all experiments were then performed with this `low-dose' regimen.
Rotarod performance
DAT±/± mice acquired maximal performance on the rotarod task more
slowly than DAT+/+, but did not differ from DAT+/+ at the end of the
training procedure (Fig. 1A). To avoid the potential bias that may
have been induced by size difference between DAT+/+ and DAT±/±
mice (femur size 1.55 6 0.02 cm vs. 1.46 cm 6 0.01, P = 0.0007),
the performance of DAT±/± mice were also compared to 6-week old
DAT +/+ mice with an identical femur size (1.46 cm + 0.01)
(Fig. 1B). Performance of 6-week old DAT+/+ mice did not differ
from that of adult DAT+/+ mice.
Five days after the end of 3-NP intoxication, the rotarod
performance was signi®cantly impaired in DAT±/± compared to
wild type mice (±64.4%, P = 0.02), DAT±/± and DAT+/+ control and
baseline values (±56.7%, P < 0.01, Fig. 1B). Such altered perform-
ances were not due to the short size of the femur, as demonstrated by
using 6-week-old DAT+/+ control mice. DAT+/+ mice intoxicated
with the `high-dose' regimen also exhibited signi®cant alteration of
rotarod performances (P < 0.05) (Fig. 1B).
Histopathology
Following the `high-dose' regimen, 8/12 DAT+/+ mice displayed
circumscribed striatal lesions. With the `low-dose' regimen, there
were no lesions but striatal surfaces revealed signi®cantly reduced
anterior striatal surfaces in DAT±/±(3-NP) mice [±16.6% and ±13.3%
at levels 1 and 2, P < 0.01 and P < 0.05, respectively, (Table 1)], as
well as a reduction in striatal volume (±9.7% compared to DAT+/+(3-
NP), P < 0.05). The absolute number of neurons within the striatum
as well as the mean numerical density were both reduced signi®cantly
in 3-NP-treated DAT±/± mice (respectively: ±11.5%, P < 0.001 at 5%
and 1% alpha error and ±12.5%, P < 0.001 at 5% and 1% alpha
error). There was no signi®cant difference in neuronal density
between all groups within the NAc. The mean number of GFAP-
 3-NP toxicity in DAT knock-out mice 2055

FIG. 1. Rotarod performances. (1A) Acquisition of rotarod task (5 r.p.m) during consecutive daily 10-trial sessions. *P < 0.05 between DAT+/+ and ±/± mice.
(1B) Mean time spent on rotating rod per trial in 6-week-old DAT+/+, DAT+/+ treated with the `high-dose' regimen and DAT+/+ and DAT±/± treated with the
`low-dose' regimen. *P = 0.02 between DAT±/±(PBS) and DAT±/±(3-NP). #P = 0.004 between baseline and postintoxication performances in DAT±/± mice.

TABLE 1. Histopathology

Mice groups

DAT+/+ (PBS) DAT+/+ (3-NP) DAT±/± (PBS) DAT±/± (3-NP)

Striatal surface level 1 (mm2) 4.29 6 0.15 4.26 6 0.12 3.85 6 0.16 3.55 6 0.15²
Striatal surface level 2 (mm2) 4.64 6 0.13 4.65 6 0.10 4.31 6 0.15 4.03 6 0.18²
Striatal surface level 3 (mm2) 5.44 6 0.08 5.21 6 0.04 5.13 6 0.06 4.67 6 0.51
Striatal surface level 4 (mm2) 3.72 6 0.47 3.73 6 0.10 3.82 6 0.06 3.40 6 0.12
Striatal volume (mm3) 6.82 6 0.117 6.51 6 0.077 6.335 6 0.065 5.88 6 0.254²
Striatal neuronal density (neurons/mm2) 1166 6 47.09 1165 6 41.20 1076 6 18.21 952.2 6 22.79*²²
Absolute number of neurons 5415 6 268 5439 6 273 4626 6 129 4045 6 182²²
GFAP-+ve cells (cells per striatal section) 134.1 6 16.8 162.6 6 16 139.4 6 9.34 215.1 6 11.8*²
Neurons in SNc 90.83 6 4.21 93.63 6 2.92 102.6 6 4.54 90.6 6 3.19*
SDH activity (mean OD) 0.354 6 0.010 0.2721 6 0.012* 0.343 6 0.0098 0.2969 6 0.010*

Striatal surface assessments were calculated in mm2 on two adjacent sections, striatal volume in mm3, absolute number of striatal neurons per section and per
striatum. Striatal neuronal density is expressed in number of neurons per mm2, and the mean number of neurons in the mesencephalon, per SNc and per
mesencephalic plane. Striatum level 1, Bregma +1.18 mm; striatum level 2, Bregma +0.98 mm; striatum level 3, Bregma +0.26 mm; striatum level 4 (Bregma
±0.22 mm). Mean glial ®brillary acid protein stained cells are expressed per striatal section. SDH activity is expressed as mean optical density (OD) for each group.
*P < 0.05 within the same genotype (either PBS or 3-NP treated). ²P < 0.05, ²²P < 0.001, within treatment groups (3-NP, PBS, either in DAT+/+ or DAT±/±).

positive glial cells was signi®cantly greater in DAT±/± mice treated
with 3-NP (+54.3%, P < 0.01 compared with DAT±/±(PBS) and
+33.2%, P < 0.05 compared to DAT+/+(3-NP). Estimation of the
number of TH-immunoreactive neurons of the mid-SNc also
demonstrated a slight but signi®cant reduction in the number of
neurons (±7%, P = 0.03) in DAT±/±(3-NP) mice.
SDH activity
In both genotypes, 3-NP induced a signi®cant reduction in SDH
activity [±13.4% in DAT±/± and ±21.3% in DAT+/+ mice, P < 0.05,
(Table 1)] compared to controls. There was no signi®cant difference
in SDH activity reduction between 3-NP-injected DAT+/+ and DAT±/±
mice.
Discussion
The DAT is responsible for rapid uptake of DA and consequently
plays a major role in regulating the temporal and spatial actions of
DA (Jaber et al., 1997). Thus, DAT knock-out mice are a relevant
model to assess the consequences of constitutive hyperdopaminergia
on striatal neurons (Jaber et al., 1997).
The present data show that DAT±/± hyperdopaminergic mice
display increased sensitivity to 3-NP, as suggested by the hypothesis
that dopamine-mediated toxicity is enhanced in `sick' neurons (Jakel
& Maragos, 2000). In mice, 3-NP produces an acute, early oxidative
stress followed by apoptotic striatal neuronal death in the following
days (Kim & Chan, 2001). C57Bl/6 mice are sensitive to systemic 3-
NP and display circumscribed striatal lesions providing the total
injected dose is suf®cient (Fernagut et al., 2002b). DAT mice are of
mixed genetic background (C57Bl/6 3 sv129) and are also sensitive
to 3-NP, as shown here.
In an exploratory experiment with a `high-dose' regimen of 3-NP
intoxication, we were confronted with a high mortality rate, which
may have been of a systemic nature (Gabrielson et al., 2001), thereby
preventing us from accurately demonstrating a speci®c striatal effect.
For this reason, the study was performed using a `low-dose' schedule
in order to prevent excessive mortality in DAT±/± mice.
A sensorimotor integration de®cit on the rotarod task following
low doses of 3-NP was observed only in DAT±/± mice. This task is
considered very sensitive to striatal dysfunction and thus has been
used as the main sensitivomotor integration test in the most recent
studies in the transgenic mouse model of HD (Ferrante et al., 2000).
The behavioural de®cit observed was independent of their reduced
size (Bosse et al., 1997), as demonstrated by using 6-week-old DAT+/+
mice as controls having the same femur size as adult DAT±/± mice.
DAT±/±(3-NP) mice displayed signi®cantly reduced striatal
volume, anterior striatal surfaces, striatal numerical density and
absolute striatal neuronal cell number compared to controls and
DAT+/+ mice. Although of limited extent, we believe that this effect

ã 2002 Federation of European Neuroscience Societies, European Journal of Neuroscience, 15, 2053±2056
2056 P.-O. Fernagut, et al.
is consistent, as it was found by studying volume, surfaces and cell
counts and proved to be signi®cant at both 5% and 1% ®rst degree
alpha error. Moreover, no difference was observed in the numerical
density of neurons in the NAc, so this effect seems speci®c to the
striatum. Additionally, glial activation was more marked in
DAT±/±(3-NP) mice. This effect was not due to variations in 3-NP
bioavailability or its primary effect as SDH inhibition was not
statistically different between DAT+/+and DAT±/± mice.
Surprisingly, dopaminergic neurons of the SNc were somewhat
more vulnerable to 3-NP in DAT±/± mice, although they are known to
be resistant to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
due to the lack of its intracellular transport by the DAT (Bezard et al.,
1999). Dopaminergic nigrostriatal projections and terminals have
been shown to be very sensitive to locally applied 3-NP (Waldner
et al., 2001), and there is also some evidence that 3-NP could induce
dopaminergic cell toxicity in vivo and in vitro by inhibiting
mitochondrial SDH (Zeevalk et al., 1995a, b; Johnson et al., 2000).
Taken together, our results provide new evidence that striatal
neurons in DAT±/± mice, and perhaps to a lesser extent, dopaminergic
neurons, are more vulnerable to mitochondrial respiratory comprom-
ise. Elevated life-long extracellular dopamine levels in these mice
(®vefold) could have exacerbated 3-NP toxicity via dopamine
receptors (Reynolds et al., 1998; Calabresi et al., 2001) or through
dopamine metabolites generating reactive oxygen species (Jakel &
Maragos, 2000). These ®ndings would seem to be clinically relevant
in view of other data on striatal dysfunction in cocaine and
methamphetamine abusers (Ernst et al., 2000; Volkow et al., 2001),
a setting resembling the prolonged life-long excessive striatal
dopamine transmission observed in DAT±/± mice.
Acknowledgements
The authors thank M. G. Caron and B. Giros for providing the initial
heterozygote mating couples and for constant support. Special thanks to Dr P.
Costet from the transgenic animal facility at Universite V. Segalen Bordeaux 2
and to M. Nosten-Bertrand and E. Morice for animal care and genotyping.
This work was supported by CNRS, INSERM and Region Aquitaine.
Abbreviations
3-NP, 3-nitropropionic acid; DA, dopamine; DAT, Dopamine transporter;
DAT±/±, dopamine transporter knock-out mice; DAT+/+, wild type mice;
GFAP, glial ®brillary acid protein; HD, Huntington's disease; Nac, nucleus
accumbens; PBS, Phosphate buffered saline; PFA, paraformaldehyde; SNc,
substantia nigra pars compacta; SDH, succinate dehydrogenase; SND,
striatonigral degeneration; TH, tyrosine hydroxylase.
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