Metab Brain Dis (2018) 33:99–105

https://doi.org/10.1007/s11011-017-0126-x

ORIGINAL ARTICLE

Dopamine D1 receptor activation maintains motor coordination

and balance in rats
Alberto Avila-Luna 1 & Arturo Gálvez-Rosas 1 & Alfredo Durand-Rivera 1 &
Laura-Elisa Ramos-Languren 2 & Camilo Ríos 2 & José-Antonio Arias-Montaño 3 &
Antonio Bueno-Nava 1

Received: 28 November 2016 / Accepted: 9 October 2017 / Published online: 19 October 2017
# Springer Science+Business Media, LLC 2017

Abstract Dopamine (DA) modulates motor coordination,
and its depletion, as in Parkinson’s disease, produces motor
impairment. The basal ganglia, cerebellum and cerebral cortex
are interconnected, have functional roles in motor coordina-
tion, and possess dopamine D1 receptors (D1Rs), which are
expressed at a particularly high density in the basal ganglia. In
this study, we examined whether the activation of D1Rs mod-
ulates motor coordination and balance in the rat using a beam-
walking test that has previously been used to detect motor
coordination deficits. The systemic administration of the
D1R agonist SKF-38393 at 2, 3, or 4 mg/kg did not alter the
beam-walking scores, but the subsequent administration of the
D1R antagonist SCH-23390 at 1 mg/kg did produce deficits in
motor coordination, which were reversed by the full agonist
SKF-82958. The co-administration of SKF-38393 and SCH-
23390 did not alter the beam-walking scores compared with
the control group, but significantly prevented the increase in
beam-walking scores induced by SCH-23390. The effect of
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11011-017-0126-x) contains supplementary
material, which is available to authorized users.
* Antonio Bueno-Nava
abueno@inr.gob.mx
1
División de Neurociencias, Instituto Nacional de Rehabilitación Luis
Guillermo Ibarra Ibarra, SSa, Calz México-Xochimilco 289,
14389 Ciudad de México, Mexico
2
Departamento de Neuroquímica, Instituto Nacional de Neurología y
Neurocirugía Manuel Velasco Suárez, SSa, Insurgentes Sur 3877,
14269 Ciudad de México, Mexico
3
Departamento de Fisiología, Biofísica y Neurociencias, Centro de
Investigación y de Estudios Avanzados del IPN, Av. IPN 2508,
07360 Ciudad de México, Mexico
the D1R agonist to prevent and reverse the effect of the D1R
antagonist in beam-walking scores is an indicator that the
function of D1Rs is necessary to maintain motor coor-
dination and balance in rats. Our results support that
D 1 Rs mediate the SCH-23390-induced deficit in motor
coordination.
Keywords Dopamine . Striatum . D1 receptor . Motor
coordination
Introduction
The cerebral cortex, basal ganglia and cerebellum are brain
areas involved in skilled movements (Mendoza and Merchant
2014) and establish reciprocal interconnections by the
cortico-basal ganglia-thalamo-cortical, basal ganglia-cer-
ebellar, cerebello-basal ganglia, cortico-ponto-cerebellar
and cerebello-thalamo-cortical pathways (Bostan and Strick
2010; Daskalakis et al. 2004; Mendoza and Merchant 2014).
The basal ganglia and cerebellum both have roles in the exe-
cution and learning of motor programs (Doya 2000), functions
modulated by dopamine (DA) (Chagniel et al. 2012). Previous
reports have described movement dysfunctions in basal
ganglia disorders (Takakusaki et al. 2008), such as the
alterations in gait and balance observed in Parkinson’s
and Huntington’s diseases (Dalton et al. 2013; Grabli et al.
2013). Notably, the restoration of physiological biochemical
conditions in Parkinson’s disease via treatment with L-DOPA
produces positive or negative changes during movement
(Curtze et al. 2015).
The striatum is the main input nucleus of the basal ganglia,
receives dopaminergic afferents form the substantia nigra pars
compacta (SNc) (Bjorklund and Dunnett 2007), and possesses
high levels of dopamine D 1-like and D2-like receptors,
100
predominantly the D1 (D1R) and D2 (D2R) subtypes (Bergson
et al. 1995). The density of dopamine receptors in the cerebel-
lum is not comparable to that present in the basal ganglia
(Camps et al. 1990), but both D1Rs and D2Rs are expressed
in the cerebellar cortex (Barili et al. 2000). Dopaminergic
transmission is associated with motor coordination, and pre-
vious results have shown that the administration of antago-
nists such as the D1R antagonist SCH-23390 impairs motor
coordination (Agmo and Soria 1999); however, the role of
D1Rs in motor coordination remains unclear. In this study,
we examined whether D1R activation modulates motor coor-
dination and balance in the rat using the beam-walking test,
previously shown to detect motor coordination deficits (De
Vasconcelos et al. 2006).
Materials and methods
Subjects
Adult male Wistar rats (280–310 g) were provided by the
UPEAL-Bioterio/UAM-Xochimilco, acclimatized to labora-
tory conditions and maintained on a 12 h/12 h light/dark cycle.
All experimental procedures were conducted in accordance
with the recommendations of the Guide for the Care and
Use of Experimental Animals (Olfert et al. 1993). We used
the minimum possible number of animals needed according to
the bioethical and statistical criteria established by Festing
(1994), and all procedures were approved by the Instituto
Nacional de Rehabilitación Animal Care Committee.
Experimental design
To examine the effects of different doses of the D1R partial
agonist SKF-38393, twenty Wistar rats were allocated to four
groups that received doses of 0, 2, 3 and 4 mg/kg
(intraperitonelly), with five rats per group. To determine the
effect of the D1R antagonist SCH-23390, twenty Wistar rats
were allocated to four groups that received doses of 0, 1, 1.5, 2
and 3 mg/kg, with five rats per group. To examine the effect of
the co-administration of the D1R agonist and antagonist, twen-
ty Wistar rats were allocated to four groups of five rats each: 1)
control (injection of vehicle solution); 2) SCH-23390 alone
(1 mg/kg); 3) SKF-38393 alone (2 mg/kg); and 4) co-
administration of SKF-38393 (2 mg/kg) and SCH-23390
(1 mg/kg). Thirty min after each pharmacological treatment
animals were evaluated with the beam-walking test. The con-
centrations of SKF-38393 and SCH-23390 used in this study
were based on previous reports (Agmo and Soria 1999; Avila-
Luna et al. 2015; Bueno-Nava et al. 2012).
To confirm whether the effect of SKF-38393 persisted after
the subsequent administration of SCH-23390, ten Wistar rats
received SKF-38393 (2 mg/kg) followed by SCH-23390
Metab Brain Dis (2018) 33:99–105
(1 mg/kg), administered 30 min after the D1R agonist. To
examine whether the effect of SCH-23390 persisted after the
subsequent administration of the full D1R agonist SKF-82958,
five rats received SCH-23390 (3 mg/kg) followed by SKF-
82958 (3 mg/kg), administered 15 min after the D 1 R
antagonist.
All three drugs, R(+)-SCH-23390 hydrochloride, (±)-SKF-
38393 hydrochloride and (±)-SKF-82958 hydrobromide
(Sigma-Aldrich, Mexico City, Mexico), were dissolved in de-
ionized water and administered (i.p.) at doses of 0.1 mL/100 g.
Motor coordination analysis
Thirty min after administration of the drugs, motor coordina-
tion was evaluated using the beam-walking test, used for the
quantification of motor deficit, according to a previously re-
ported protocol (Bueno-Nava et al. 2010), which is briefly
described as follows: each rat was evaluated on four sections
of a wooden beam (2 m long, 2.5 cm wide) elevated at 50 cm
above the floor. Rats with no apparent deficit obtained a motor
score of 0. An animal that widened its base and presented four
toes off the beam bilaterally received a score of 1, with a score
of 2 assigned if the animal limped with one hind limb
(hypotonus). An animal with at least 3 slips and/or 4 toes off
the beam (unilaterally) received a score of 3. Animals with
falls or more of 3 slips received a score of 4. Rats that dragged
a limb obtained a score of 5, and those unable to run received a
score of 6. Finally, the scores received on the four sections
were summed (maximum score 24). Each rat was videotaped
during traversals and the videotapes were revised by an inves-
tigator blind to the treatment.
Spontaneous motor activity
Twenty Wistar rats were allocated to four groups: 1) control
(injection of vehicle solution); 2) SCH-23390 alone
(1 mg/kg); 3) SKF-38393 alone (4 mg/kg); and 4)
SKF-38393 (4 mg/kg) and SCH-23390 (1 mg/kg).
Spontaneous motor activity was recorded using an
Auto-Track Opto-Varimex activity monitoring system
(Columbus Instruments, Columbus, OH, USA) placed inside
an anechoic chamber (42.2 × 42.5 × 20.5 cm). All groups were
monitored in four sessions of one min per session and each rat
was registered by separate in the activity chamber. Results of
distance travelled and horizontal counts were normalized and
expressed as percentage of change with respect to the time
zero min post drug.
Statistical analysis
All values are expressed as means ± SEM. Statistical analysis
of the beam-walking test and spontaneous motor activity was
performed with the nonparametric Kruskal-Wallis test
Metab Brain Dis (2018) 33:99–105
followed by the Mann-Whitney U-test to compare the mean
rank of the treatment groups. For two related samples, the
Wilcoxon test was also applied when comparing the ranks of
means between drug treatments. Differences between the ex-
perimental conditions were regarded to be statistically signif-
icant at P < 0.05.
Results
Effects of different doses of the D1R agonist and antagonist
As shown in Fig. 1, the beam-walking scores obtained 30 min
after the systemic treatment with the D1R agonist SKF-38393
at 2, 3 or 4 mg/kg did not significantly differ from those in the
appropriate control group. In contrast, the systemic adminis-
tration of the D1R antagonist SCH-23390 at 1, 1.5, 2 and
3 mg/kg significantly increased the beam-walking scores by
4.25 (P ≤ 0.005), 4.90 (P = 0.005), 5.00 (P = 0.003) and 5.00
(P = 0.003) fold, respectively, compared with the control
group (Fig. 1).
Effect of the co-administration of the D1R antagonist
and agonist
Figure 2 shows that the systemic administration of SCH-
23390 alone at 1 mg/kg significantly increased the beam-
walking scores by 3.80 fold in comparison to the control
group (P ≤ 0.005). The administration of SKF-38393 alone
(2 mg/kg) did not produce a significant effect, but when co-
administered with SCH-23390 prevented the increase in the
beam-walking score induced by the antagonist.
Fig. 1 Effect of the systemic administration of the D1R agonist SKF-
38393 and the antagonist SCH-23390 on motor coordination deficits
evaluated with the beam-walking test. Values are expressed as means ±
SEM. Statistical analysis was performed with the nonparametric Kruskal-
Wallis test followed by the Mann-Whitney U-test to compare the mean
rank of the drug treatment groups. **, P < 0.005 compared with the
control group
101
Fig. 2 Effects of systemic administration of SCH-23390 alone, SKF-
38393 alone and the co-administration of SKF-38393 + SCH-23390 on
motor coordination deficits evaluated with the beam-walking test. Values
are expressed as means ± SEM. Statistical analysis was performed with
the nonparametric Kruskal-Wallis test followed by the Mann-Whitney U-
test to compare the mean rank of the drug treatment groups. **, P < 0.005,
compared with the control group
Effect of SKF-38393 and the subsequent administration
of SCH-23390
The systemic administration of the agonist SKF-38393
at 2 mg/kg did not significantly alter the beam-walking
scores compared to the pre-drug condition (Fig. 3a).
However, these low scores did not persist after the sub-
sequent administration of SCH-23390, with beam-
walking scores of 3.37-fold (P = 0.021) and 3.58-fold
(P = 0.019) of the control values, at 15 or 30 min after
drug administration, respectively. The effect of SCH-
23390 was not prevented by a higher dose of SKF-38393
(3 mg/kg; data not shown), but the subsequent administration
of the full D1R agonist SKF-82958 at 3 mg/kg reversed the
increase in the beam-walking score induced by SCH-23390
(3 mg/kg; Fig. 3b).
Effect of SKF-38393, SCH-23390 and their
co-administration in spontaneous motor activity
As shown in Fig. 4a, the administration of SCH-23390 alone
at 1 mg/kg significantly decreased the spontaneous motor ac-
tivity evaluated as distance travelled (−46%, −48 and −54% at
20, 40 and 60 min, respectively; P < 0.05 for all values) and
horizontal counts (−29%, −34%, −70% at 20, 40 and 60 min,
respectively; P < 0.05 for all values), but the rats were still
capable to walk in the chamber (Fig. 4b). The effect of SCH-
23390 alone was prevented by the co-administration of the
D1R agonist SKF-38393 (4 mg/kg; Fig. 4a–b). The adminis-
tration of SKF-38393 alone at 4 mg/kg significantly increased
both the distance travelled (+62% at 40 min; P = 0.008) and
the horizontal counts (+39% at 40 min; P = 0.028). The sys-
temic administration of SKF-38393 alone at 1 and 2 mg/kg
did not produce a significant difference in both distance trav-
elled and horizontal counts (data not shown).
102
Fig. 3 Effect of the sequential administration of the D 1 R
antagonist SCH-23390 and the D 1 R agonists SKF-38393 and
SKF-82958 on motor coordination deficits evaluated with the
beam-walking test. a Effect of the administration of the partial
D1R agonist SKF-38393 and the subsequent administration of
the D1R antagonist SCH-23390 on motor coordination deficits. b
Effect of the administration of the D1R antagonist SCH-23390
and the subsequent administration of the full D1R agonist SKF-
82958 on motor coordination deficits. In panels a and b, values
are expressed as means ± SEM. Statistical analysis was performed
using the Wilcoxon test for two related samples. **, P < 0.05,
when compared with SKF-38393 and SKF-82958; SKF-82958
was not different from vehicle
Effect of SKF-38393, SCH-23390 and their
co-administration in the time and speed of traversal
Figure 5 shows that the administration of SCH-23390
alone significantly increased the time of traversal in
the beam-walking by 7 fold in comparison to the ve-
hicle group. In contrast, the administration of SCH-
23390 + SKF-38393 and SKF-38393 alone did not
alter the time of traversal compared with the control
group (Fig. 5a). As shown in the Fig. 5b, the admin-
istration of SCH-23390 significantly decreased the
speed of traversal in the beam-walking by 5.57 fold
compared with the control group, whereas, the admin-
istration of SCH-23390 + SKF-38393 and SKF-38393
alone did not alter the speed of traversal compared
with the vehicle group.
Metab Brain Dis (2018) 33:99–105
Discussion
The systemic administration of 2, 3 or 4 mg/kg of the D1R
agonist SKF-38393 alone did not alter the beam-walking scores;
however, the co-administration at 2 and 4 mg/kg with the D1R
antagonist SCH-23390 blocked the antagonist-induced effects
on the beam-walking scores and spontaneous motor activity. We
previously reported that the systemic co-administration of SKF-
38393 and SCH-23390 (both at 1 mg/kg) prevented the increase
in striatal DA levels induced by the antagonist (1 mg/kg) dose.
This result indicates that the systemic co-administration of the
D1R agonist attenuated the effects of the antagonist SCH-23390,
via a competitive action (Bueno-Nava et al. 2012). Our evalua-
tion of the spontaneous motor activity showed that SKF-38393
at 4 mg/kg significantly increased both the distance travelled
and the horizontal counts (Fig. 4a and b), and that the effect of
the D1R agonist was prevented by the co-administration of
SCH-23390. Further, the selective blockade of D1Rs with
SCH-23390 alone increased beam-walking scores, and this ef-
fect was prevented by the co-administration of SKF-38393 at
2 mg/kg (Fig. 2). These results indicate that the effect of the
agonist on beam-walking scores resulted from the action of
D1Rs to maintain motor coordination and balance, which may
explain why the subsequent administration of the antagonist
SCH-23390 increased beam-walking scores, reverted by the full
D1R agonist SKF-82958.
Previous results showed that the D1R agonist SKF-38393, at
a wide range of higher doses (5–25 mg/kg), induced a syn-
drome of motor hyperactivity characterized by grooming,
sniffing and rearing (Imperato et al. 1987; Molloy and
Waddington 1984). In this study, the agonist was administered
at 2, 3 and 4 mg/kg to reduce the factors associated with motor
hyperactivity induced by SKF-38393, and our results showed
that the doses used did not interfere with the beam-walking test.
A previous report documented that the systemic adminis-
tration of dopamine receptor antagonists impaired motor co-
ordination (Agmo and Soria 1999). Our results showed that
the SCH-23390-induced effect on beam-walking scores was
prevented and reversed by co-administration of the D1R ago-
nists SKF-38393 and SKF-82958, respectively, confirming
that the effect of SCH-23390 on beam-walking scores was
mediated by D1Rs. However, the administration of SKF-
38393 did not prevent the effect of SCH-23390 (Fig. 3a); this
result can be explained by different agonist efficacy, because
SKF-38393 and SKF-82958 are partial and full agonists, re-
spectively (Fig. 3b) (Andersen and Jansen 1990; Izenwasser
and Katz 1993). In our study the administration of SKF-82958
alone (>1 mg/kg) interfered with the beam-walking test, and
we therefore used SKF-38393 in the respective treatment. We
consider that the best explanation for this is that the adminis-
tration of SKF-82958 alone, at lower doses (0.1–2 mg/kg),
induces the syndrome of motor hyperactivity (Wang and
McGinty 1996), which is induced by SKF-38393 at
Metab Brain Dis (2018) 33:99–105 103

Fig. 4 Effect of the systemic

administration of SCH-23390
alone, SKF-38393 alone and the
co-administration of SKF-
38393 + SCH-23390 on distance
traveled and horizontal counts in
the spontaneous motor activity
monitor. a Representative maps
for the distance traveled in each
treatment obtained at 40 min after
drug administration. b Analysis of
the groups. Values are expressed
as means ± SEM. Statistical anal-
ysis was performed using the
nonparametric Kruskal-Wallis
test followed by the Mann-
Whitney U-test to compare the
mean rank of the drug treatment
groups. *, P < 0.05; **, P < 0.02;
***, P < 0.01; when compared
with vehicle

higher doses (5–25 mg/kg) (Imperato et al. 1987; Molloy and
Waddington 1984).
In this study, the administration of SCH-23390 alone sig-
nificantly decreased spontaneous motor activity in both dis-
tance travelled and horizontal counts (Fig. 4a), but the rats
were still able to walk in the chamber (Fig. 4b). The effect
of SCH-23390 alone (1 mg/kg) on spontaneous motor activity
is indicative of a motor dysfunction, as reported previously by
Agmo and Soria (1999). During the beam-walking test, we
observed that the systemic administration of the D1R antago-
nist SCH-23390 decreased motor coordination and the speed
of traversal, but the rats completed the test at least for some
sections of the elevated wooden beam and increased the time
of traversal. The effect of SCH-23390 on the beam-walking
test can thus be associated to the decrease in spontaneous
motor activity induced by the lowest dose of SCH-23390
(1 mg/kg) used in our study, blocked by the co-
administration of SKF-38393. We therefore propose that the
effects of the D1R antagonist SCH-23390 are associated with
motor coordination deficits. Our results indicate that D1R ac-
tivation by DA is necessary to maintain motor coordination
and balance. Previously studies have shown that other neuro-
transmitters and their receptors contribute to motor coordina-
tion in the striatum. For example, histamine and the H3 recep-
tor, which in the last few years has been pointed out as key
modulator of dopaminergic transmission and striatal modula-
tor of motor control and coordination (Nowak et al. 2008;
Rapanelli 2017; Rapanelli et al. 2016).

Fig. 5 Effect of the systemic administration of control (injection of traversal in the beam-walking. Values are expressed as the
vehicle solution, n = 5), SCH-23390 alone (1 mg/kg, n = 5), SKF- mean ± SEM. Statistical analysis was performed using one-way
38393 alone (2 mg/kg, n = 5) and the co-administration SCH-23390 + ANOVA followed by Dunnett’s test. Significantly different from vehicle:
SKF-38393 (1 mg/kg; 2 mg/kg, n = 5) on time (a) and speed (b) of *, P < 0.05
104
As mentioned in the BIntroduction^ section, the basal gan-
glia and cerebellum are interconnected (Bostan and Strick
2010) and both possess dopamine receptors, with the basal
ganglia containing a higher density of the D1R and D2R sub-
types (Bergson et al. 1995; Camps et al. 1990; Surmeier et al.
1996). In addition, the basal ganglia and cerebellum are in-
volved in motor control, required for coordinating different
movements (Doya 2000), and both structures also have mul-
tiple connections with the cerebral cortex (Daskalakis et al.
2004; Mendoza and Merchant 2014). Although the cerebral
cortex contains a lower density of D1Rs than do the basal
ganglia (Camps et al. 1990), it responds to changes in dopa-
mine levels, thereby resulting in motor dysfunction (Costa
et al. 2006). According to the classical view of Albin et al.
(1989), the increase in the beam-walking scores after the ad-
ministration of the D1R antagonist SCH-23390 observed in
our study may be indicative of inhibition of the thalamo-
cortical pathway and the consequent inability for motor coor-
dination (Costa et al. 2006).
As a limitation of this study, it is well-known that the drugs
employed have different effects when administered systemi-
cally versus locally, and we therefore cannot discard the pos-
sibility that our results for the beam-walking test include some
concomitant effects on motor coordination after the total acti-
vation and/or blockade of dopamine D1Rs.
In conclusion, our results showed that D1Rs mediated the
SCH-23390-induced deficits in motor coordination and spon-
taneous motor activity. The SCH-23390-induced increase in
beam-walking scores was prevented and reverted by the co-
administration of SKF-38393 and SKF-82958, respectively,
and these results support that D1Rs mediated the SCH-
23390-induced effect in motor coordination deficit. The effect
of SCH-23390 on the beam-walking test can be associated to
the decrease in spontaneous motor activity, blocked by the co-
administration of SKF-38393. Together, our results indicate
that D1R function is necessary to maintain motor coordination
and balance in rats.
Acknowledgements The authors thank Dr. Iván Pérez-Neri for his as-
sistance in performing the recordings of spontaneous activity. We thank
MVZ Hugo Lecona Butrón for support with the housing, care, mainte-
nance and monitoring of the health of the experimental animals in the
institute (INR-LGII). We thank MVZ Javier Pérez Gallaga for technical
support.
References
Agmo A, Soria P (1999) The duration of the effects of a single adminis-
tration of dopamine antagonists on ambulatory activity and motor
coordination. J Neural Transm (Vienna, Austria : 1996) 106:219–
227. https://doi.org/10.1007/s007020050152
Albin RL, Young AB, Penney JB (1989) The functional-anatomy of basal
ganglia disorders. Trends Neurosci 12:366–375. https://doi.org/10.
1016/0166-2236(89)90074-x
Metab Brain Dis (2018) 33:99–105
Andersen PH, Jansen JA (1990) Dopamine receptor agonists - selectivity
and dopamine-D1 receptor efficacy. Eur J Pharmacol Mol Pharm
Sect 188:335–347. https://doi.org/10.1016/0922-4106(90)90194-3
Avila-Luna A, Prieto-Leyva J, Galvez-Rosas A, Alfaro-Rodriguez A,
Gonzalez-Pina R, Bueno-Nava A (2015) D-1 antagonists and
D-2 agonists have opposite effects on the metabolism of do-
pamine in the rat striatum. Neurochem Res 40:1431–1437.
https://doi.org/10.1007/s11064-015-1611-4
Barili P, Bronzetti E, Ricci A, Zaccheo D, Amenta F (2000)
Microanatomical localization of dopamine receptor protein immu-
noreactivity in the rat cerebellar cortex. Brain Res 854:130–138.
https://doi.org/10.1016/s0006-8993(99)02306-9
Bergson C, Mrzljak L, Smiley JF, Pappy M, Levenson R, Goldman-Rakic
PS (1995) Regional, cellular, and subcellular variations in the distri-
bution of D1 and D5 dopamine receptors in primate brain. J
Neurosci Off J Soc Neurosci 15:7821–7836
Bjorklund A, Dunnett SB (2007) Dopamine neuron systems in the brain:
an update. Trends Neurosci 30:194–202. https://doi.org/10.1016/j.
tins.2007.03.006
Bostan AC, Strick PL (2010) The cerebellum and basal ganglia are inter-
connected. Neuropsychol Rev 20:261–270. https://doi.org/10.1007/
s11065-010-9143-9
Bueno-Nava A, Gonzalez-Pina R, Alfaro-Rodriguez A, Nekrassov-
Protasova V, Durand-Rivera A, Montes S, Ayala-Guerrero F
(2010) Recovery of motor deficit, cerebellar serotonin and lipid
peroxidation levels in the cortex of injured rats. Neurochem Res
35:1538–1545. https://doi.org/10.1007/s11064-010-0213-4
Bueno-Nava A, Gonzalez-Pina R, Alfaro-Rodriguez A, Avila-Luna A,
Arch-Tirado E, Alonso-Spilsbury M (2012) The selective inhibition
of the D-1 dopamine receptor results in an increase of metabolized
dopamine in the rat striatum. Neurochem Res 37:1783–1789.
https://doi.org/10.1007/s11064-012-0790-5
Camps M, Kelly PH, Palacios JM (1990) Autoradiographic localization
of dopamine D 1 and D 2 receptors in the brain of several mamma-
lian species. J Neural Transm Gen Sect 80:105–127. https://doi.org/
10.1007/bf01257077
Chagniel L, Robitaille C, Lacharite-Mueller C, Bureau G, Cyr M (2012)
Partial dopamine depletion in MPTP-treated mice differentially al-
tered motor skill learning and action control. Behav Brain Res 228:
9–15. https://doi.org/10.1016/j.bbr.2011.11.019
Costa RM, Lin S-C, Sotnikova TD, Cyr M, Gainetdinov RR, Caron MG,
Nicolelis MAL (2006) Rapid alterations in corticostriatal ensemble
coordination during acute dopamine-dependent motor dysfunction.
Neuron 52:359–369. https://doi.org/10.1016/j.neuron.2006.07.030
Curtze C, Nutt JG, Carlson-Kuhta P, Mancini M, Horak FB (2015)
Levodopa is a double-edged sword for balance and gait in
people with Parkinson's disease. Mov Disord 30:1361–1370.
https://doi.org/10.1002/mds.26269
Dalton A, Khalil H, Busse M, Rosser A, van Deursen R, Olaighin
G (2013) Analysis of gait and balance through a single tri-
axial accelerometer in presymptomatic and symptomatic.
Huntington's Dis Gait & Posture 37:49–54. https://doi.org/
10.1016/j.gaitpost.2012.05.028
Daskalakis ZJ, Paradiso GO, Christensen BK, Fitzgerald PB, Gunraj C,
Chen R (2004) Exploring the connectivity between the cere-
bellum and motor cortex in humans. J Physiol 557:689–700.
https://doi.org/10.1113/jphysiol.2003.059808
De Vasconcelos AP, Klur S, Muller C, Csquer B, Lopez J, Certa U, Cassel
JC (2006) Reversible inactivation of the dorsal hippocampus by
tetrodotoxin or lidocaine: a comparative study on cerebral functional
activity and motor coordination in the rat. Neuroscience 141:1649–
1663. https://doi.org/10.1016/j.neuroscience.2006.05.023
Doya K (2000) Complementary roles of basal ganglia and cerebellum in
learning and motor control. Curr Opin Neurobiol 10:732–739.
https://doi.org/10.1016/s0959-4388(00)00153-7
Metab Brain Dis (2018) 33:99–105
Festing MF (1994) Reduction of animal use: experimental de-
sign and quality of experiments. Lab Anim 28:212–221.
https://doi.org/10.1258/002367794780681697
Grabli D et al (2013) Gait disorders in parkinsonian monkeys
with Pedunculopontine nucleus lesions: a tale of two sys-
tems. J Neurosci 33:11986–11993. https://doi.org/10.1523/
jneurosci.1568-13.2013
Imperato A, Mulas A, Di Chiara G (1987) The D-1 antagonist
SCH 23390 stimulates while the D-1 agonist SKF 38393
fails to affect dopamine release in the dorsal caudate of free-
ly moving rats. Eur J Pharmacol 142:177–181. https://doi.org/
10.1016/0014-2999(87)90672-8
Izenwasser S, Katz JL (1993) Differential efficacies of dopamine D1
receptor agonists for stimulating adenylyl-cyclase in squirrel-
monkey and rat. Eur J Pharmacol Mol Pharm Sect 246:39–44.
https://doi.org/10.1016/0922-4106(93)90007-v
Mendoza G, Merchant H (2014) Motor system evolution and the emer-
gence of high cognitive functions. Prog Neurobiol 122:73–93.
https://doi.org/10.1016/j.pneurobio.2014.09.001
Molloy AG, Waddington JL (1984) Dopaminergic behavior stereospecif-
ically promoted by the D1 agonist r-sk-and-f-38393 and selectively
blocked by the D1 antagonist SCH-23390. Psychopharmacology
82:409–410. https://doi.org/10.1007/bf00427697
Nowak P et al (2008) Histamine H(3) receptor ligands modulate L-
DOPA-evoked behavioral responses and L-DOPA-derived
105
extracellular dopamine in dopamine-denervated rat striatum.
Neurotox Res 13:231–240
Olfert E, Cross B, Mc William A (1993) Guide for the care and use of
experimental animals. Can Council Animal Care 1:211
Rapanelli M (2017) The magnificent two: histamine and the H3
receptor as key modulators of striatal circuitry. Prog Neuro-
Psychopharmacol Biol Psychiatry 73:36–40. https://doi.org/
10.1016/j.pnpbp.2016.10.002
Rapanelli M, Frick LR, Horn KD, Schwarcz RC, Pogorelov V, Nairn AC,
Pittenger C (2016) The histamine H3 receptor differentially modu-
lates mitogen-activated protein kinase (MAPK) and Akt signaling in
Striatonigral and Striatopallidal neurons. J Biol Chem 291:21042–
21052. https://doi.org/10.1074/jbc.M116.731406
Surmeier DJ, Song WJ, Yan Z (1996) Coordinated expression of dopa-
mine receptors in neostriatal medium spiny neurons. J Neurosci Off
J Soc Neurosci 16:6579–6591
Takakusaki K, Tomita N, Yano M (2008) Substrates for normal gait and
pathophysiology of gait disturbances with respect to the basal gan-
glia dysfunction. J Neurol 255:19–29. https://doi.org/10.1007/
s00415-008-4004-7
Wang JQ, McGinty JF (1996) Scopolamine augments C-fos and ZIF/268
messenger RNA expression induced by the full D-1 dopamine re-
ceptor agonist SKF-82958 in the intact rat striatum. Neuroscience
72:601–616. https://doi.org/10.1016/0306-4522(95)00597-8