Neuroscience Letters 389 (2005) 30–34

Alteration of striatal [11C]raclopride and6-[18F]fluoro-l-3,4-dihydroxyphenylalanine uptake precedes developmentof methamphetamine-induced rotation following unilateral
6-hydroxydopamine lesions of medial forebrain bundle in rats
Yasushi Ishida a,∗ , Keiichi Kawai c , Yasuhiro Magata b,d , Hiroshi Abe a ,Mitsuyoshi Yoshimoto c , Ryuichiro Takeda a , Hiroyuki Hashiguchi a ,Takahiro Mukai b,e , Hideo Saji b
a Department of Psychiatry, Miyazaki Medical College, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki-gun, Miyazaki 889-1692, Japanb Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University,

Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japanc Department of Radiological Technology, School of Health Sciences, Faculty of Medicine, Kanazawa University,

5-11-80 Kodatsuno, Kanazawa 920-0942, Japand Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu University School of Medicine,

1-20-1 Handayama, Hamamatsu 431-3192, Japane Department of Chemo-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University,

3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Received 8 April 2005; received in revised form 15 June 2005; accepted 28 June 2005

Abstract
We studied the positron emission tomography (PET) tracer distributions of ligands for dopamine D1 receptors ([11 C]SCH23390) and D2
receptors ([11 C]raclopride) and of the dopamine precursor analog 6-[18 F]fluoro-l-3,4-dihydroxyphenylalanine ([18 F]FDOPA) in the brain after
6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle in rats. The number of methamphetamine-induced rotation was higher
at 14 days than at 3 days after the 6-OHDA lesions. The brains of 6-OHDA-treated rats were analyzed by tissue dissection following i.v.
bolus of each tracer at 3 days (acute stage) or 3 weeks (chronic stage) postlesion. [11 C]Raclopride, but not [11 C]SCH23390, showed higher
accumulation in the striatum on the lesion side than on the non-lesion (intact) side both at 3 days and 3 weeks postlesion. On the other hand,lower accumulation of [18 F]FDOPA was observed in the striatum on the lesion side at 3 days postlesion and in both the striatum and cerebral
cortex on the lesion side at 3 weeks postlesion. Our studies demonstrate that an increase in [11 C]raclopride and a decrease in [18 F]FDOPA
uptake in the denervated striatum is evident even at 3 days after the 6-OHDA lesions when the methamphetamine-induced rotational behavior
is not established.
© 2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: 6-Hydroxydopamine; Striatum; [11 C]Raclopride; 6-[18 F]Fluoro-l-3,4-dihydroxyphenylalanine; Methamphetamine-induced rotation; Rat

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesionsof the medial forebrain bundle (MFB), through which thenigrostriatal pathway and mesocorticolimbic pathway projectfrom the ventral midbrain [21], develop contralateral sensory∗ Corresponding author. Tel.: +81 985 85 2969; fax: +81 985 85 5475.

E-mail address: ishiday@med.miyazaki-u.ac.jp (Y. Ishida).
0304-3940/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.neulet.2005.06.060

neglect as well as postural and motor asymmetry, which arecharacterized by spontaneous and drug-induced rotation of
the animal [29]. The 6-OHDA rat has been widely used as an
animal model of Parkinson’s disease, the clinical features ofwhich are dominated by bradykinesia, rigidity, tremors, postural instability, and dementia [20]. In this model, there is animmediate and almost complete destruction of the dopamine

Y. Ishida et al. / Neuroscience Letters 389 (2005) 30–34

neurons of the substantia nigra and ventral tegmental area,
resulting in near total depletion (2% of normal) of dopaminein the ipsilateral striatum as a result of 6-OHDA injections[10]. An immunohistochemical study showed that after 6OHDA injections there is no evident damage to dopaminergic neurons and fibers in the contralateral side of the brain[10,12]. There have been several reports on the enhanced
effects of directly acting dopamine agonists, such as apomorphine in rotational behavior after the unilateral 6-OHDA
lesions. The rotational behavior induced by dopamine agonists has been attributed to postsynaptic dopamine receptor
supersensitivity in the striatum that occurs following theunilateral destruction of mesostriatal dopamine fibers [31].
Based on these observations, it is conceivable that the 6OHDA-lesioned rat model may be useful for evaluating brain
functions in Parkinson’s disease.
6-[18 F]Fluoro-l-3,4-dihydroxyphenylalanine([18 F]FDOPA) is a positron-emitting analog of the dopamine
precursor l-DOPA and is one of the earliest [18 F]-labeled
compounds, which is proposed as an imaging agent for external in vivo examination of the central nervous dopaminergic
system [6]. Therefore, [18 F]FDOPA has been used as an
imaging agent to investigate the activity of aromatic aminoacid decarboxylase in the striatum and to assess the integrityof the dopaminergic system in the living brain by using
positron emission tomography (PET) [7]. We previously
demonstrated upregulation of dopamine D2 receptors in the
striatum and decrease in FDOPA uptake in both the striatum
and cerebral cortex at 3 weeks after the 6-OHDA lesions inthis model rat [11]. However, little information is available
with regard to changes in dopamine receptors and FDOPA
uptake in the brain, particularly, during the acute stage that
follows the 6-OHDA lesions under the same experimental
conditions.
Therefore, in the present study, we studied thetracer distributions of ligands for dopamine D1 receptors([11 C]SCH23390) and D2 receptors ([11 C]raclopride), andof [18 F]FDOPA in the brain at 3 days and 3 weeks after the
6-OHDA lesions of the MFB in rats. Furthermore, to correlate
the degree of motor symptoms with the tracer distributions
at two different point of time, rotational behavior inducedby methamphetamine challenge was sequentially evaluated
3 and 14 days after the 6-OHDA lesions.
The subjects were male Wistar rats (Kiwa Laboratory
Animals, Kaisou, Japan), weighing 120–130 g at the beginning of the experiment. The experimental protocols used inthis study were approved by the ethics committees for animal experimentation at Miyazaki Medical College and Kyoto
University. Sixty rats were anesthetized using pentobarbital(40 mg/kg, i.p.), and unilateral lesions of the left MFB werecreated by injecting 12 ␮g 6-OHDA hydrobromide (Sigma,
St. Louis, MO, USA) in 4 ␮l sterile saline containing 0.01%
ascorbic acid. Stereotaxic coordinates for the lesions were as
follows: AP 3.2 mm rostral to the interaural line, L 1.3 mm
left of midline, and V 6.7 mm ventral to the dural surface,with the incisor bar set 2.4 mm below the level of the ear bars

31[14]. For analyzing tracer distributions in the brains of the
6-OHDA-treated rats, 30 rats were used at 3 days and theremaining 30 rats were used at 3 weeks 6-OHDA postlesion.
Nine rats were randomly selected from the latter group of 30
rats, and the number of rotation following methamphetamine(3 mg/kg, i.p.) challenge was evaluated at 3 and 14 days after
the 6-OHDA lesions [10,12]. In addition to the 60 6-OHDAtreated rats, seven rats were used as sham-lesioned animals
for the behavioral experiment. Sham lesions were created byinjecting the same amount (4 ␮l) of saline into the left MFB
as described above.
[11 C]SCH23390 was synthesized by [11 C]methylation
reaction of SCH24518 in an automated synthesis apparatus (CUPID C-100, Sumitomo Heavy Industries Co.
Ltd., Tokyo, Japan), according to the method reported by
Halldin et al. [9] with a slight modification. The radiochemical purity of [11 C]SCH23390 was >97.4%. The specific activity of the product was 38.5–81.4 GBq/␮mol.
[11 C]Raclopride was synthesized by [11 C]methylation reaction of O-desmethylraclopride in the CUPID C-100. The
radiochemical purity of [11 C]raclopride was >98.4%. The
specific activity of the product was 32.6–88.9 GBq/␮mol.
[18 F]FDOPA was synthesized in a multipurpose synthetic
system [18], according to the method reported by Namavari etal. [22] with a slight modification. The radiochemical purityof [18 F]FDOPA was >98.5%. The specific activity of the
product was 33.0–33.7 MBq/␮mol.
The regional distribution of radioactivity in the rat
brain was examined after i.v. injection of [11 C]SCH23390,[11 C]raclopride, or [18 F]FDOPA at 3 days and 3 weeks 6OHDA postlesion. In previous studies, many investigators
reported that degeneration of nigral dopaminergic neurons aswell as dopamine receptor supersensitivity in the denervatedstriatum was established in 3 weeks 6-OHDA postlesion[19,32]. One hour (for [11 C]SCH23390 and [11 C]raclopride)or 1.5 h (for [18 F]FDOPA) after the i.v. injection, the rats
were killed by decapitation, and each side of the brain was
dissected into different brain regions (striatum, cerebral cortex, cerebellum, etc.) on ice as described by Glowinski andIversen [8]. The brain samples were weighed and radioactivity accumulation of each tracer was determined for eachbrain region bilaterally. Radioactivity was measured usinga scintillation counter (model 5003, Packard, USA). First,
results were expressed as radioactivity per unit wet tissue
weight (cpm/g). Next, the biodistribution of [11 C]SCH23390,[11 C]raclopride, and [18 F]FDOPA was computed as a ratio oflesion side to intact side for each brain region of the 6-OHDA
rats.
Two-way ANOVA with repeated measures was used to statistically analyze the data for the methamphetamine-induced
rotation. When significant differences were found between
groups and/or time effects (P < 0.05), post-hoc comparisonswere performed by the Newman–Keuls test. Data of the ratioof lesion side to intact side for each brain region were analyzed non-parametrically by the Wilcoxon signed rank test.
Furthermore, the Mann–Whitney U-test was used to analyze

32

Y. Ishida et al. / Neuroscience Letters 389 (2005) 30–34
Table 1
Biodistribution of each tracer in three brain regions of the 6-OHDA rats
Three daysThree weeks

Cerebral cortex
Striatum
Cerebellum

1.00 ± 0.02
0.97 ± 0.03
1.03 ± 0.02

1.10 ± 0.05
1.10 ± 0.04
1.00 ± 0.01

[11 C]raclopride (n = 10)
Cerebral cortex
Striatum
Cerebellum

1.06 ± 0.05
1.61 ± 0.09**
1.07 ± 0.05

1.11 ± 0.06
1.90 ± 0.10**
1.01 ± 0.02

[18 F]FDOPA (n = 10)
Cerebral cortex
Striatum
Cerebellum

0.99 ± 0.04
0.74 ± 0.05**
0.95 ± 0.07

0.90 ± 0.06*
0.81 ± 0.03**
0.99 ± 0.01

[11 C]SCH23390 (n = 10)

Fig. 1. The mean number of rotations (±S.E.M.) per min recorded over a 60min test period in response to methamphetamine (3 mg/kg, i.p.) is shown forunilaterally 6-OHDA-lesioned (n = 9) and sham-lesioned rats (n = 7). “ipsi(+)” and “contra (−)” refer to the direction of rotation with respect to thelesion side. * P < 0.05, compared to each corresponding value of the shamlesioned animals (ANOVA followed by Newman–Keuls test). $ P < 0.05,
compared to the value at 3 weeks after 6-OHDA lesioning for each group(ANOVA followed by Newman–Keuls test).

the difference between the ratio at 3 days and 3 weeks postlesion for each tracer and each brain region. P-values of <0.05
were regarded as significant.
When compared with the sham-lesioned animals,
methamphetamine induced significant elevated number ofrotations ipsilateral to the 6-OHDA injections at both3 and 14 days postlesion in the 6-OHDA rats (groupeffect, F1,14 = 24.00, P < 0.01; Newman–Keuls test, P < 0.05)(Fig. 1). Furthermore, the number of methamphetamineinduced rotation, in the 6-OHDA group, was significantly
higher at 14 days than at 3 days after the 6-OHDA lesions(time effect, F1, 14 = 7.94, P < 0.05; Newman–Keuls test,
P < 0.05) (Fig. 1).
Table 1 shows the biodistribution of [11 C]SCH23390,
11[ C]raclopride, and [18 F]FDOPA in the three brain regions(cerebral cortex, striatum, and cerebellum) on the lesion sideof the 6-OHDA rats, which is represented as the radioactivity
ratio in the lesion side relative to the intact side of the brain,
at 3 days and 3 weeks after the 6-OHDA lesions. The biodistribution of [11 C]raclopride in the striatum was significantly
higher (Wilcoxon signed rank test, P < 0.01) on the lesionside than on the intact side of the 6-OHDA rats both at 3 daysand 3 weeks postlesion. On the other hand, the biodistributionof [18 F]FDOPA in the striatum was lower (Wilcoxon signed
rank test, P < 0.01) on the lesion side than on the intact sideat both 3 days and 3 weeks postlesion. The biodistribution of[18 F]FDOPA in the cerebral cortex was lower on the lesionside than on the intact side at 3 weeks after the 6-OHDA
lesions (Wilcoxon signed rank test, P < 0.05). None of thethree regions showed any significant difference in the biodistribution of [11 C]SCH23390 between the lesion and intact
sides of the brain at 3 days and 3 weeks after the 6-OHDA
lesions.

Each value presents a ratio (mean ± S.E.M.) of lesion side to intact side ofeach brain region (cpm/g) of the 6-OHDA rats (lesion side/intact side). No
difference was observed between the ratio at 3 days and at 3 weeks postlesion
for any brain region with respect to the three tracers (Mann–Whitney U-test).
* P < 0.05.
** P < 0.01 vs. corresponding values of intact side (Wilcoxon signed rank
tests).

No difference was observed between the ratio at 3 days
and at 3 weeks postlesion for any brain region with respect
to the three tracers (Mann–Whitney U-test).
This study showed that the unilateral MFB lesions
produced with 6-OHDA caused methamphetamine-induced
rotation ipsilateral to the lesions both at 3 and 14 days
postlesion. However, the number of rotation was lower at
3 days than that at 14 days postlesion. Similar findings
were also reported by Labandeira-Garcia et al. [15]. They
showed that there is a marked and progressive loss of
dopaminergic terminals for a few days after the 6-OHDA
lesions. This loss is counteracted by factors acting at bothpresynaptic and postsynaptic levels. There is rapid development of dopamine receptor supersensitivity, detected within
24–48 h of lesions (indicated by rotational behavior andstriatal Fos expression induced by apomorphine). Additionally, dopamine is more easily released in the lesion side bymethamphetamine at the time of lesions; this response is possibly accompanied by decreased dopamine reuptake. This
leads to stronger dopamine stimulation of the denervatedstriatum when methamphetamine is administered during thefirst week postlesion. These might be the possible explanations for the delayed alteration of methamphetamine-induced
rotation when compared with the alteration in tracer distributions in the present study.
Here, the biodistribution of [11 C]SCH23390 did notchange in any brain region of the 6-OHDA-treated animals
within 3 weeks postlesion. An upregulation of dopamine D1
receptors after the MFB lesions has been demonstrated inreceptor autoradiographic studies [5,23]. Furthermore, supersensitivity of dopamine D1 receptors has been reported in
the striatal tissue homogenates after the MFB lesions with
6-OHDA [3,26]. In contrast, there are other contradicting
results showing no change or decrease in density of striatal
dopamine D1 receptors after denervation of the nigrostri-Y. Ishida et al. / Neuroscience Letters 389 (2005) 30–34

atal dopaminergic pathway [16,28]. The precise reason forthese discrepancies is unknown, but the discrepancies may
be related to the differences in the methods (e.g. radioligand
binding assay, autoradiography) used and/or different time
points considered after 6-OHDA lesioning in the earlier studies.
In previous studies, it was observed that denervation of
the nigrostriatal pathway can cause supersensitivity of thepostsynaptic population of dopamine D2 receptors [5,23].
Furthermore, Araki et al. also observed that the upregulation of D2 receptors was more pronounced than thatof D1 receptors in the striatum after 6-OHDA lesioning[1,2]. These observations are consistent with our present
findings.
The present study also showed that [18 F]FDOPA uptake
significantly decreased in the striatum 3 days postlesion, andin both the striatum and cerebral cortex 3 weeks postlesion.
A lowered capacity of dopamine synthesis was observed not
only in the striatum but also in the cerebral cortex on the lesionside during the chronic stage. The [18 F]FDOPA uptake in the
cerebral cortex has been reported to increase [13] or decrease[27] in patients with Parkinson’s disease. When this is considered along with the evidence that the degree of dopamine
denervation in the 6-OHDA-treated animals was almost complete [10], the present findings suggest that the [18 F]FDOPA
uptake in the cerebral cortex may decrease in parkinsonian
patients in an advanced stage. Further studies on the tracer
distributions in rats with partial 6-OHDA lesions may clarify
the issue.
As reviewed by Laruelle, numerous independent laboratories have established that [11 C]raclopride behaves aspredicted by the occupancy model, i.e., higher synaptic
dopamine levels are associated with lower ligand binding
and vice versa [17]. In view of the occupancy model, an
increase in [11 C]raclopride and a decrease in [18 F]FDOPA
uptake in the denervated striatum may, at least in part, be due
to endogenous dopamine reduction.
As we previously reported, the present study demonstrated
an increase in [11 C]raclopride uptake in the striatum and adecrease in FDOPA uptake in both the striatum and cerebral
cortex ipsilateral to the 6-OHDA lesions at 3 weeks postlesion[11]. Furthermore, this study revealed that the similar findings, such as an increase in [11 C]raclopride and a decrease in
FDOPA uptake in the denervated striatum, are already evident
at 3 days postlesion. Although contradicting results have also
been obtained previously [4,30], other studies using in vivo
binding methods have reported proliferation of D2 receptors
as early as 4 days after 6-OHDA injections [24,25], and theseresults may be related to our findings.
In conclusion, the present study demonstrates an increasein [11 C]raclopride and a decrease in FDOPA uptake in the
denervated striatum both 3 days and 3 weeks following the 6OHDA lesions. Therefore, the combination of a D2 antagonist
and FDOPA may provide a potentially useful method forassessing the effects of dopamine depletion in Parkinson’s
disease.

33

Acknowledgements
This research was supported by Grants-in-Aid for Scientific Research (14370273, 16591145) and 21st Century COE
programs in Miyazaki Medical College and in Hamamatsu
University School of Medicine from the Japan Society for
the Promotion of Science.

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