Behavioural Brain Research 275 (2014) 114–119

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Behavioural Brain Research

journal homepage: www.elsevier.com/locate/bbr

Short Communication

Place conditioning to apomorphine in rat models of Parkinson’s

disease: Differences by dose and side-effect expression
Joannalee C. Campbell a , Shiveindra B. Jeyamohan b , Priscilla De La Cruz b , Nita Chen b ,
Damian Shin a , Julie G. Pilitsis a,b,∗
a
Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
b
Department of Neurosurgery, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA

h i g h l i g h t s

• Rats underwent a dopaminergic unilateral lesion or sham surgery.

• All rats underwent place conditioning to either a low or high dose of apomorphine.
• Lesioned rats preferred low dose apomorphine while shams did not.
• Lesioned rats were divided on preferring high dose apomorphine; shams preferred it.
• Increased apomorphine side-effects negatively correlated with place conditioning.

a r t i c l e i n f o a b s t r a c t

Article history: One potential complication of treating Parkinson’s Disease (PD) with dopaminergic drugs is dopamine
Received 21 May 2014 dysregulation syndrome, an addiction-like response to the drug therapy. Here, we assessed whether rats
Received in revised form 11 July 2014 given parkinsonian-like symptoms with a unilateral injection of 6-hydroxydopamine into the medial
Accepted 1 September 2014
forebrain bundle (6-OHDA-MFB), exhibit similar behavior. To examine this, we injected these rats or
Available online 6 September 2014
sham-lesioned rats subcutaneously (sc) with apomorphine (APO) at low (0.05 mg/kg) and high (1 mg/kg)
dosage and monitored their conditioned place preference Saline was administered on alternating days.
Keywords:
After 4 and 8 conditioned pairings, both rat groups underwent post-conditioning tests in a drug-free
Dopamine dysregulation syndrome
Dopamine agonist
state 6-OHDA rats exhibited positive place conditioning to the low dose of APO after 4 and 8 pairings
6-hydroxydopamine whereas sham-lesioned rats did not (p < 0.01). At the high APO dose, sham-lesioned rats showed con-
Hemiparkinsonian sistent positive place conditioning, but preferences in 6-OHDA rats were more variable although they
all exhibited rotation behavior. Upon further inspection, we noted that contraversive rotation increased
over time and this negatively correlated with place conditioning scores. While the absolute number of
rotations did not negatively affect preference for the APO-paired chamber, an increase in rotation num-
bers between pairings did (r = −0.634, p = 0.027). Taken together, 6-OHDA rats were more sensitive to the
rewarding aspects of APO, but the adverse consequence of rotation diminished this response This model
may be ideal to study addiction-like responses in PD.
© 2014 Elsevier B.V. All rights reserved.

Parkinson’s disease (PD) is a neurodegenerative disease result-
ing from the death of dopaminergic neurons in the substantia nigra
pars compacta (SNc). Currently, there are no treatments that will
cure PD; however drug therapies are used to treat motor symp-
toms Generally, once patients become bothered by their PD motor
symptoms, they initiate treatment either with dopaminergic drugs
∗ Corresponding author at: Department of Neurosurgery, MC 10 47 New Scotland
Avenue Albany, NY 12208 Tel.: +1 518 262 5314; fax: +1 5182620902.
E-mail address: pilitsj@mail.amc.edu (J.G. Pilitsis).
(levodopa) or dopamine agonists (e.g. pramipexole, ropinirole, apo-
morphine). Patients treated with these drugs have been noted to
develop impulsive/compulsive behaviors including dopamine dys-
regulation syndrome (DDS), which includes compulsive overuse of
medication, cyclic mood disorders dependent upon medication sta-
tus, and refusal to discontinue high doses of medication despite
severe social and physical consequences [1]. The current reported
incidence of DDS is 3–4% of the PD population [2], but this preva-
lence may be an underestimate since DDS, similar to any addiction,
is likely underreported by the patients due to the patients’ desire
outweighing the self-destructive outcomes.

http://dx.doi.org/10.1016/j.bbr.2014.09.002
0166-4328/© 2014 Elsevier B.V. All rights reserved.
 J.C. Campbell et al. / Behavioural Brain Research 275 (2014) 114–119
There have been a few assessments of drug reward in rodent
models of dopamine loss. Using the conditioned place preference
(CPP) paradigm, groups have found increased place preference to
pramipexole in a bilateral 6-hydroxydopamine (6-OHDA) striatal
lesion rodent model of PD [3], and increased place preference to
levodopa alongside a decrease in preference for a natural reward
in an ␣-synuclein rat model of PD [4]. Others used CPP to probe the
rewarding properties of D1, D2, and D3 receptor agonists in rats
injected with 6-OHDA bilaterally in the medial forebrain bundle
(MFB). It was noted that D2 and D3 receptor agonists produced
rewarding effects [5]. Finally, others evaluated various dopamine
receptor agonists in CPP using a less traditional bilateral 6-OHDA
posterior ventral tegmental area lesion rodent model, and found
that only drugs with D2 or D3 receptor activity produced a place
preference [6].
While the literature has so far determined that some rodent
models of PD show increased place preference to certain dopamine
agonists, this was not examined in rats injected unilaterally with
6-OHDA in the MFB; notably, this is a commonly used animal
model of PD which better mirrors the severe motor deficits seen
in later stages of PD than rats with bilateral striatal lesions, there
are well-established behavioral tests to gauge dopamine loss, and
this rat model of PD does not produce the mortality seen with
bilateral 6-OHDA MFB or SNc injection [7]. Mortality rates due to
adipsia and aphagia for bilateral 6-OHDA MFB/SNc models have
improved over the decades, but even substantial post-operative
interventions cannot prevent premature death in a percentage of
rats (e.g. [16,17]). Further, the unilateral 6-OHDA MFB lesion rat
can be used to model global changes such as depression [18], and
will rotate in the direction of the impaired forelimb when given
levodopa or dopamine agonists and this rotation behavior sensi-
tizes over time [8,9]. This results in very high levels of involuntary
activity for the rat. Thus, this rat model of PD provides the oppor-
tunity to probe the balance between drug reward and aversive
motor side-effects, and how that balance changes over dose and
time. With these considerations in mind, we assessed CPP to the
D1/D2 receptor agonist apomorphine (APO) in rats with unilat-
eral 6-OHDA MFB injections at low (0.05 mg/kg) and high (1 mg/kg)
dosage after either 4 or 8 pairings of the novel environment with
the drug.
Male Sprague-Dawley rats arrived at >200 g bodyweight
(Taconic, Germantown, NY) and were placed in a climate con-
trolled vivarium maintained on a 12 h light/dark cycle (lights on
7:00 am) with ad libitum access to food and water One week
later, rats were injected with 6-OHDA (n = 30) or saline (sham-
lesioned, n = 12) unilaterally in the MFB. Procedures were similar
to those discussed in [10], including the use of desipramine HCl
(25 mg/kg; Sigma, St Louis, MO) and pargyline HCl (50 mg/kg;
Sigma, St Louis, MO) prior to surgical site preparation, craniotomy
and a burr hole above the MFB: 44 mm posterior to bregma, 21 mm
lateral from midline, 8 mm ventral Rats received 12 ␮g of 6-OHDA
(Sigma, St Louis, MO; dissolved in saline containing 0.01% ascor-
bic acid) at a rate of 0.5 ␮l/min Penicillin (22000 IU/kg; King
Pharmaceuticals, Inc, Bristol, TN) and buprenoprhine (0.1 mg/kg;
Reckitt Benskiser Pharmaceuticals, Inc, Richmond, VA) were post-
operatively injected sc, and buprenophine administration was
continued every 12 h for 2 additional days for analgesia.
Two weeks later, rats underwent the limb-use asymmetry
test Rats were placed into a clear plexiglass cylinder and filmed
for 5 min, and the number of wall touches with each forepaw
was recorded A bias towards using the paw ipsilateral to the 6-
OHDA lesion indicates that the lesion has been effective, with
>80% of the touches coming from that paw highly correlating
with a >80% reduction in the dopamine content of the lesioned
side of the brain [10,11]. Only rats showing a >80% ispilateral
paw touch bias (“6-OHDA”) and sham rats without any bias
115
underwent CPP testing This resulted in n = 11 sham and n = 19
6-OHDA rats meeting the criteria to advance to CPP testing
(Fig. 1A).
For CPP, the conditioning apparatus (70 × 25 × 50 cm)
consisted of three chambers, with the two larger end cham-
bers (30 × 25 × 50 cm each) used for conditioning sessions. The
chambers were distinguished by tactile and odor cues; one of
the two end chambers had bar flooring and an almond scent,
the other had grid flooring and a rose scent, and the unpaired
small center chamber had solid flooring and no odor pairing.
Pretests showed that rats did not prefer one end chamber and its
cues over the other. Further testing with naïve rats (n = 7) with
saline paired with both sides showed that there was no significant
change in the percentage of time spent on either end chambers
in a post-test after 4 saline conditioning sessions (40.2% vs 351%)
or 8 conditioning sessions (371% vs 399%). During conditioning
sessions (30 min, once daily) rats were confined to the assigned end
chamber immediately post-injection (sc APO at 0.05 or 1 mg/kg, or
equivalent volume of saline). However, during test days rats could
freely traverse the 3 distinct chambers. There were 8 conditioning
sessions for saline and APO. Rats were videotaped during pretest
and two post-conditioning test sessions (10 min duration each,
one after the 4th pairing and one after the 8th pairing), and the
amount of time spent in each chamber was noted. The raw amount
of time spent on each side was used to determine the conditioning
score (post-test minus the pre-test time spent on the same side; all
times in seconds). The number of clockwise and counter-clockwise
rotations was counted during the 30 min sessions.
After experiments were completed, dopaminergic cell body and
axon degeneration were confirmed by tyrosine hydroxylase (TH)
immuno-staining. Rats were anesthetized with an intraperitoneal
injection of urethane and transcardially perfused with 150 ml of
cold 0.9% saline with 2 units/ml heparin, followed by 150 ml of a
4% paraformaldehyde solution. After removal, brains were post-
fixed in 4% paraformaldehyde for 24 h before being stored in a 30%
sucrose solution A cryostat (Microm HM500M) was used to acquire
coronal brain sections at 60 ␮m, with free floating sections from
the striatum and SNc/VTA collected for TH immunohistochemistry,
similar to described in [10]. Briefly, sections were quenched in
3% H2 O2 for 10 min, placed overnight at 4 ◦ C into blocking solu-
tion (10% normal goat serum [NGS, Jackson ImmunoResearch, West
Grove, PA] and 0.2% Triton-X [Sigma, St Louis, MO] in 0.1 M PBS),
transferred to 10% NGS in PBS with a 1:1000 concentration of anti-
TH antibody (rabbit polyclonal; Santa Cruz Biotech, Dallas, TX) for
the next 2 days at 4 ◦ C, placed in 10% NGS in PBS with a 1:500
concentration of peroxidase-conjugated goat anti-rabbit (Jackson
ImmunoResearch, West Grove, PA) for 1 h, and finally developed
in 3,3 -Diaminobenzidine (DAB) solution (Vector labs, Burlingame,
CA) before mounting onto slides Images were taken under 10x
magnification on a Zeiss Axio Imager M.2 microscope fitted with
a Hamamatsu ORCA-Flash40 camera using Neurolucida 1101 soft-
ware (MBF Bioscience, Williston, VT) and montaged to create one
image per section Comparison of TH immuno-reactive area in the
right vs left striatum and SNC was done using ImageJ (NIH free-
ware, VER 148). Sham-lesioned rats did not exhibit differences
in TH immuno-reactivity between hemispheres, whereas 6-OHDA
rats had marked reduction in TH expression in the striatum and
SNc/VTA on the6-OHDA injected side compared to the un-injected
side (118% ± 253% of striatal TH, 398% ± 797% of VTA, 65% ± 289%
of SNc TH content in injected side when compared to un-injected
side; Fig. 1B).
The place conditioning scores were analyzed by repeated meas-
ures ANOVA. The relationship between rotation behavior and APO
conditioning score was examined using the Pearson correlation
coefficient. All data are expressed as mean ± standard error of
means (SEM).
116 J.C. Campbell et al. / Behavioural Brain Research 275 (2014) 114–119

Fig. 1. Confirmation of 6-OHDA phenotype.

A. The results of the limb-use asymmetry test Rats with parkinsonian-like symptoms will preferentially use the forepaw ipsilateral to the lesion site to explore their
environment (> 80% ipsilateral use).
B. An example of TH immuno-staining in the striatum and SNc. The hemisphere injected with 6-OHDA is indicated by the arrows, where marked loss of dopamine terminals
(striatum) and cell bodies (SNc) are apparent.

If rats showed no preference above their individual base- respectively. On the 0.05 mg/kg dose of APO, 6-OHDA rats (n = 7)
line times to a chamber the preference score would equal had a conditioning score of 8980 ± 3138 on the post-test after 4th
0. Rats with decreased or increased time on the APO-paired pairings, and a conditioning score of 120.22 ± 3310 on the post-
side would have a negative and positive conditioning score, test after 8th pairings In contrast, sham rats injected with this dose
 J.C. Campbell et al. / Behavioural Brain Research 275 (2014) 114–119
Fig. 2. Conditioning scores of 6-OHDA rats and sham-lesioned rats to low and high
doses of APO.
A. The conditioning scores of 6-OHDA and sham-lesioned rats to 0.05 mg/kg APO.
Significant difference is present between the groups across both time-points; 6-
OHDA rats show a positive conditioning score to APO while shams do not. B. The
conditioning scores of 6-OHDA rats and sham-lesioned rats to 1 mg/kg APO. Aster-
isks indicate significance at p < 0.01
(n = 5) had a conditioning score of −8259 ± 2401 and −8640 ± 3177
on the 4th and 8th pairings post-test, respectively. Therefore, a sig-
nificant difference between 6-OHDA and sham-lesioned rats was
present in APO conditioning score since the former showed a higher
positive place conditioning score than the latter (F1,10 = 22632,
p < 0.01); however, no difference was seen with time (Fig. 2A). Com-
paring these groups to the expected mean of 0 (no change in side
preference), both the 6-OHDA group (t13 = 471, p < 0.05) and the
sham group (t9 = −450, p < 0.05) are significantly different from a
condition of no change. With saline conditioning scores, we also
noted a significant difference between 6-OHDA and sham-lesioned
rats (F1,10 = 16570, p < 0.01).
On the 1 mg/kg dose of APO, 6-OHDA rats (n = 12) had a condi-
tioning score of 1720 ± 5177 on the post-test after the 4th pairing,
and a conditioning score of −7956 ± 5113 on the post-test after
the 8th pairing Sham-lesioned rats given the same dose (n = 6) had
a conditioning score of 9531 ± 1363 and 9845 ± 2264 on the post-
test after the 4th and 8th pairing, respectively. A two-way repeated
measures ANOVA on APO conditioning scores did not reveal any sig-
nificant differences between 6-OHDA and sham groups or between
117
Fig. 3. Rotation behavior versus APO conditioning score.
A. The change in rotations towards the lesioned forelimb between the 4th and 8th
pairing versus the change in the conditioning score during the same time Negative
correlation is present B. A photograph of a 6-OHDA rat exhibiting rotation behavior
with 1 mg/kg APO conditioning in CPP apparatus.
the two time-points (Fig. 2B). Comparing these groups to the
expected mean of 0, the 6-OHDA group was not significantly dif-
ferent from 0 while the sham group was (t11 = 769, p < 0.05). While
positive conditioning scores remained stable in sham animals,
there were diverse responses in 6-OHDA rats. When we further ana-
lyzed the APO conditioning scores in 6-OHDA rats, we found that 3
animals exhibited a positive conditioning score to the APO-paired
side after the 4th (16141 ± 7612) and 8th pairings (160.58 ± 3957).
Four 6-OHDA rats changed from a positive conditioning score at
the 4th pairing (13246 ± 3601) to a negative one at the 8th pair-
ing (−10668 ± 6186). Five 6-OHDA rats had a negative conditioning
score after both pairings (−16153 ± 3757; −20195 ± 4413).
Lastly, we examined whether an interaction between rotation
behavior and conditioning scores could explain the marked vari-
ability in conditioning scores in 6-OHDA rats Sham-lesioned rats
and 6-OHDA rats on saline conditioning sessions had few rota-
tions (<15 per session) in either direction In contrast, 6-OHDA
rats given 1 mg/kg APO turned 460.42 ± 6576 (∼15 RPM) at the
4th pairing and 62833 ± 100.60 (∼21 RPM) at the 8th pairing
towards the lesioned side as shown in Fig. 3B. There was no cor-
relation between rotations and APO conditioning score on the
4th pairing post-test, and no correlation between rotations and
APO conditioning score on the 8th paring post-test. However,
we found a significant correlation between the change in rota-
tions versus the change in preference scores from the 4th to the
8th pairing (r = −0.634, p = 0.027; Fig. 3A). We also examined the
118 J.C. Campbell et al. / Behavioural Brain Research 275 (2014) 114–119
correlation between our TH measures (striatam, VTA, Snc), scores,
and rotations, but only found a significant correlation between
VTA TH and 4th pairing rotations (r = 0.768, p < 0.01). In sum-
mary, we found that 6-OHDA rats with a unilateral lesion have
a different place conditioning profile to APO compared to sham-
lesioned animals. The former will positively place condition more
than the latter at the lower APO dose. When exposed to high
dose APO, some 6-OHDA rats preferred the APO-paired side at
both pairing post-tests, others avoided that side during the entire
experiment, and some switched from a preference to an aver-
sion.
Several factors may have led to the divergence in the 6-OHDA
rats given 1 mg/kg APO for 8 pairings. For instance, subtle differ-
ences in dopamine receptor up-regulation among 6-OHDA rats
would prompt different sensitivity to APO, leading to different
propensity for rotation. Indeed, the negative correlation between
change in rotations over time and the change in APO conditioning
score suggests that the switch from chamber preference to avoid-
ance is influenced by this motor side-effect. Differences in receptor
up-regulation could be due to hemi-lesion severity, genetic or epi-
genetic differences between rats, or a combination of these. The
divergence in preference could also be due to different individual
tolerances to rotational behavior. Notably, the absolute number of
the rotations did not correlate with preference at either the 4th
or 8th pairing since animals with similar rotation numbers would
still prefer or avoid the APO-paired chamber. Instead, it appears
that the magnitude of rotation between pairings was the critical
determinant. The outbred Sprague-Dawley rat population appears
to have sufficient variation to model different levels of rotation tol-
erability within an APO-exposed group. This finding may provide
some utility in using this animal model in future studies. Further,
it is known that repeated administrations of levodopa and some
dopamine agonists produce bothersome dyskinesias in PD patients
[19]. Rodent PD models exposed to these drugs experience abnor-
mal trunk, limb, and/or orolingual movements corresponding to
the drug’s dyskinetic potential [19–21]. It would be interesting
to determine the relative contribution of these dyskinesia-related
side-effects to place preferences, and to compare dopamine ago-
nists like APO, which produce both dyskinesia-related and rotation
effects, to other dopamine agonists which do not [22].
A further finding was that sham-lesioned rats had a negative
conditioning score to APO at the low dose, but a positive one at the
high dose. This finding is not altogether surprising given the mixed
experience reported in individuals with APO administration APO is
commonly used in the veterinary field as an emetic, and although
rats do not experience emesis [23] they do display pica which is
thought to indicate a similar type of discomfort [12] and condi-
tioned taste aversion [13,14]. Yet, APO can also elicit conditioned
place preference and sustained self-administration in a subset of
normal rats despite the emergence of taste aversion [13,14]. The
mix of positive and negative effects is not uncommon among drugs
of abuse (e.g. amphetamine [14], cocaine [15]). Therefore, we spec-
ulate that the rewarding nature of APO at the higher dose was
sufficient to overcome the negative aspects of the drug in sham-
lesioned rats.
Finally, it is worth noting that APO at the low dose elicited
significant changes despite the smaller sample size as reported
elsewhere (e.g. [3]). Presumably, the more severe dopaminer-
gic degeneration in the affected hemisphere could have induced
stronger sensitivity to APO. The unilateral 6-OHDA MFB rat model of
PD has the advantage of displaying clear motor deficits reminiscent
of the PD patient population, whereas other models produce little-
to-no motor deficits. Additionally, negative side effects are seen.
With these caveats in mind, we report that 6-OHDA rats exhibit
more sensitivity to the positive effects of APO than sham-lesioned
rats, and a split in APO preference when rotation behavior emerges.
This suggests that the unilateral 6-OHDA MFB rat model of PD can
be useful for measuring changes in drug reward in a parkinson-like
system.
Acknowledgments
Financial support for this research was provided by an Albany
Medical College start-up grant to JGP.
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