SYNAPSE 62:920–926 (2008)

Differential Expression of Fos and Zif268
in the Nigrostriatal System After
Methamphetamine Administration in a Rat
Model of Parkinson’s Disease
YASUSHI ISHIDA,1* KEIICHI KAWAI,2 YASUHIRO MAGATA,3 KOSUKE EBIHARA,1
RYUICHIRO TAKEDA,1 HIROSHI ABE,1 MITSUYOSHI YOSHIMOTO,2 HIROYUKI HASHIGUCHI,1
KEI ODAGIRI,1 HISAE MATSUO,1 AND TOSHIKAZU NISHIMORI4
1
Department of Psychiatry, Faculty of Medicine, University of Miyazaki, Kiyotake-cho, Miyazaki-gun,Miyazaki 889-1692, Japan2
Department of Quantum Medical Technology, Division of Health Sciences, Graduate School of Medical Sciences,
Kanazawa University, Kanazawa 920-0942, Japan
3
Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu University School of Medicine,
Hamamatsu 431-3192, Japan
4
Division of Neurobiology, Faculty of Medicine, University of Miyazaki, Kiyotake-cho, Miyazaki-gun,Miyazaki 889-1692, Japan

KEY WORDS

6-hydroxydopamine; immediate-early gene proteins; basal ganglia;
transplantation

ABSTRACTThe goal of this study was to examine the topological speciﬁcity ofmethamphetamine-induced activation of the immediate-early gene proteins, Fos andZif268, in the nigrostriatal system in a unilateral 6-hydroxydopamine (6-OHDA) rat
model of Parkinson’s disease with or without intrastriatal grafts of fetal ventral mesencephalon. Methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity(FLI) dominantly in the striatum and the globus pallidus (GP) on the intact side as
well as in the substantia nigra pars reticulata (SNr) on the lesioned side in the 6OHDA rats. Lower levels of methamphetamine-induced FLI in the striatum and GP
on the lesioned side were restored by intrastriatal grafts which could completely suppress the methamphetamine-induced rotation. In the striatum, a similar tendency
could be observed between Fos and Zif268 immunoreactivity following methamphetamine. However, sparse immunoreactivity of Zif268 could be detected in the GP and
SNr on both sides in the 6-OHDA rats. Intrastriatal grafts had little inﬂuence on
Zif268 expression in these two regions. The differential expression of Fos and Zif268
was observed among the three regions of the nigrostriatal system following methamphetamine in the 6-OHDA rats. This may suggest that Fos and Zif268 therefore possess gene-speciﬁc and region-speciﬁc functions in the basal ganglia nuclei. Synapse
62:920–926, 2008. V 2008 Wiley-Liss, Inc.
CINTRODUCTION
Despite intensive study, the character and the function of immediate-early genes (IEGs) in the central
nervous system (CNS) have not yet been elucidated.
The induction of cellular IEGs may be a critical signaltransduction step in neuronal plasticity induced byneurotransmitters and drugs, with the protein products of IEGs functioning to either activate or repress
genes that encode the proteins involved in the differentiated functions of target neurons. The induction of
the IEG, c-fos, in the CNS has thus been proposed to
be indicative of synaptic activation, and it may also
C 2008 WILEY-LISS, INC.
V

be involved in converting short-term extracellular signals to long-term intracellular responses (Morgan andCurran, 1991; Sheng and Greenberg, 1990).
Zif268 (also known as NGFI-A, Egr-1, and Krox24), and also Fos, are transcription factors that may
Contract grant sponsor: Japan Society for the Promotion of Science.
*Correspondence to: Yasushi Ishida, Department of Psychiatry, Faculty of
Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki-gun,Miyazaki 889-1692, Japan. E-mail: ishiday@med.miyazaki-u.ac.jp
Received 24 February 2008; Accepted 30 April 2008
DOI 10.1002/syn.20558
Published online in Wiley InterScience (www.interscience.wiley.com).

FOS AND ZIF268 IN HEMIPARKINSONIAN RATS

regulate neuronal and nonneuronal gene expression
in the mammalian brain (Dragunow et al., 1989; Morgan and Curran, 1991). The transcriptional activity of
the Fos family of molecules is dependent upon themforming heterodimers, using a leucine-zipper motif,
with the Jun family of transcription factors (Kerpolla
and Curran, 1991), whereas, members of the Krox
family of transcription factors bind to DNA using azinc-ﬁnger motif (Lemaire et al., 1988, 1990).
Regional difference among ﬁve regions [caudate-putamen (CPu), globus pallidus (GP), entopeduncular nucleus, subthalamic nucleus, substantia nigra pars
reticulata (SNr)] of the basal ganglia are observed in
the basal expression of Zif268, and constitutive
expression of Zif268 occurring mainly in the
GABAergic neurons in the CPu may at least in partbe maintained by glutamatergic afferents (Ishida
et al., 2000).
Various dopaminergic and CNS stimulating drugs
such as cocaine, amphetamine, and methamphetamine have been reported to induce (or up-regulate)both the Fos and Zif268 expression in the terminal
region of the nigrostriatal dopamine (DA) system, thestriatum (Bhat et al., 1992; Hebb and Robertson,
1997; Umino et al., 1995). In rats with a unilaterallesion of the nigrostriatal DA pathway induced by the
6-hydroxydopamine (6-OHDA), systemic administration of an indirect DA agonist such as amphetamine
or methamphetamine produces ipsilateral rotational
behavior by releasing DA following the stimulation of
DA receptors in the intact side of the brain (Ungerstedt, 1971). Methamphetamine-induced rotational
behavior is accompanied by the expression of Fos-like
immunoreactivity (FLI) in the nigrostriatal components in 6-OHDA rats (Ishida et al., 1998b). This wasobserved not only in the striatum contralateral to theunilateral 6-OHDA-induced lesion in the nigrostriatal
pathway, as reported previously (Abrous et al., 1992;
Cenci et al., 1992; Robertson et al., 1989), but also in
the SNr ipsilateral to the lesion. The asymmetry in
the FLI between the hemispheres following methamphetamine treatment has also been conﬁrmed byother researchers (Hebb and Robertson, 1999; Wirtshafter and Asin, 1999).
The goal of this study was to examine the topological speciﬁcity of methamphetamine-induced activationof the IEG proteins, Fos and Zif268 in three regions(medial CPu, GP, SNr) of the nigrostriatal system ina unilateral 6-OHDA rat model of Parkinson’s disease
with or without intrastriatal grafts of fetal ventral
mesencephalon (VM). There have been few reports
concerning amphetamine- or methamphetamineinduced Zif268 expression in basal ganglia of ananimal model of Parkinson’s disease (Hebb andRobertson, 1997). In particular, the effect of intrastriatal dopaminergic transplants on the IEG expression has not yet been elucidated.

921

MATERIALS AND METHODS
Animals
Male Wistar rats (Japan SLC, Hamamatsu, Japan),weighing 120–130 g at the beginning of the experiment, were used. They were housed in a group of 3–4
rats under a 12 h light/dark cycle with free access tofood and water. The experimental protocols used inthis study were approved by the ethical committeesof animal experimentation at the University ofMiyazaki.
6-OHDA lesion and transplantation surgery
The rats were anesthetized with pentobarbital(50 mg/kg, i.p.), and unilateral lesions of the left
medial forebrain bundle (MFB) were made by the
injection of 8 lg 6-OHDA hydrobromide (Sigma, MA)
in 4 ll of sterile saline containing 0.01% ascorbic
acid. The stereotaxic coordinates for the lesions were
3.3 mm rostral to the interaural line, 1.3 mm left ofthe midline, and 6.7 mm ventral to the dural surface.
The incisor bar was set 2.4 mm below the level of theear bars (König and Klippel, 1963). The 6-OHDA solution was delivered by a microinjection pump at 1 ll/min,and the cannula was left in place for 5 min after the endof injection. In addition to the 6-OHDA-treated rats,
twelve age-matched rats were used as sham-lesioned
controls for the histological experiments. Sham lesions
were created by injecting the same amount (4 ll) of
saline into the left MFB as described above.
Neural transplantation was performed from fetal
VM tissue according to the cell suspension method(Björklund and Dunnett, 1992; Dunnett and Björklund, 1992). Six microliters of the suspension containing 4.8 3 105 cells from 15-day-old rat embryos
was injected into two sites of the denervated striatum: (1) AP 5 1.0 mm rostral to the bregma, L 5
2.5 mm left of midline, V 5 5.0 mm ventral to thedural surface, and (2) AP 5 0.0 mm caudal to thebregma, L 5 3.2 mm left of midline, V 5 5.0 mm
ventral to the dural surface (König and Klippel,
1963). All graft suspensions were injected at a rate of
1 ll/min, and the syringe was left in place for 5 minafter the end of the injection.
Rotational behavior
The motor disturbance was assessed by counting
the full-rotations per min in a cylindrical container(30-cm diameter) at 10-min intervals for the ﬁrst
60 min after methamphetamine (3 mg/kg, i.p.) administration (Nishino et al., 1990; Ungerstedt, 1971). Behavioral screening was carried out after 2 weeks recovery, and the animals that turned no less than
7 turns/min on methamphetamine challenge were
included in the study. There is an immediate andalmost complete destruction of the DA neurons of the
Synapse922

Y. ISHIDA ET AL.

substantia nigra and of the ventral tegmental area,
thus resulting in the near total depletion (2% of normal) of DA in the ipsilateral striatum to the 6-OHDA
injections (Ishida et al., 1998a). The rats were tested
again for rotational asymmetry at 7 and 15 weeks after the 6-OHDA treatment (at 4 and 12 weeks after
transplantation).
Histological procedure
Methamphetamine treatment and subsequent perfusion of the animals was carried out 4–5 months after the induction of the 6-OHDA lesion. Six agematched control rats were also included in the study
in which the rats were treated with an equal volume
of saline. Two hours after methamphetamine (3 mg/
kg, i.p.) treatment, the rats were deeply anesthetizedwith an overdose of pentobarbital and were perfusedtranscardially ﬁrst with saline followed by 4% paraformaldehyde in 0.1 M phosphate buffer (PB; pH 7.4).
The brains were removed immediately and postﬁxed
at 48C for 1 h in the above ﬁxative. After ﬁxation, thesamples were immersed at 48C for 1 h in 0.1 M PB
with 10% sucrose and cryoprotected at 48C overnightin the same buffer with 30% sucrose. The brains were
subsequently cut on a freezing microtome into 50 lm
coronal sections for immunohistochemistry. An immunohistochemical examination of Fos or Zif268 expression was performed according to the manufacturer’s
instructions for use of a streptavidin-biotin system(Histoﬁne SAB-PO(R) kit, Nichirei, Tokyo, Japan).
Brieﬂy, biotinylated secondary antibodies were
coupled with streptavidin-biotinylated horseradish
peroxidase, and the reaction was visualized using diaminobenzidine (DAB) as a chromogen enhanced bycobalt chloride. Between each incubation step, thefree-ﬂoating sections were thoroughly rinsed withphosphate-buffered saline. The antibodies for c-Fos
and Zif268 were rabbit polyclonal antisera (diluted
1:5000 and 1:3000, respectively; Santa Cruz Biotechnology, CA). For each animal and each IEG protein, 3sections through the CPu approximately 0.7 mm
rostral to the bregma, 3 sections through the GP
1.0 mm caudal to the bregma and 3 sections
through the SN 2.2 mm rostral to the interauralline were selected for quantitative analysis (König
and Klippel, 1963). Fos or Zif268 immunoreactivity inthe medial CPu, GP, and SNr was quantiﬁed bycounting the number of cells immunopositive for Fos
or Zif268, respectively, in 0.5 mm 3 0.5 mm (0.25 mm2)
squares using a 103 microscope objective. Thereafter,
the numbers obtained from the 3 sections in each area
(medial CPu, GP, or SNr) were averaged to give theresults for each animal and each IEG protein. The data
are therefore presented as the number of cells immunopositive for Fos or Zif268 per 0.25 mm2 of striatal,pallidal or nigral tissue (Ishida et al., 1998b).
SynapseFig. 1. The mean number of rotations (6SEM) per min over a
60 min test period in response to methamphetamine (3 mg/kg i.p.)
are shown for unilaterally 6-OHDA-lesioned (lesion; n 5 12) and thelesion plus grafted rats (graft; n 5 6). ‘‘ipsi (1)’’ and ‘‘contra (2)’’refer to the direction of rotation to side of lesion and transplantation. The decrease in the ipsilateral rotation found in the group
receiving fetal VM grafts in comparison to that observed in thelesioned animals was signiﬁcant at 4 and 12 weeks after transplantation (*P < 0.01, two way ANOVA with repeated measures followed
by Newman-Keuls test).

Statistical analysis
The data were analyzed by ANOVA followed bypost hoc comparisons, when appropriate, using theNewman-Keuls test or the Dunnett’s t-test. P values <0.05 were regarded as being statistically signiﬁcant.
RESULTS
Rotational behavior
Before transplantation, methamphetamine (3 mg/
kg, i.p.) induced strong ipsilateral rotation in 6OHDA-lesioned rats (mean 6 SEM 5 10.4 6 0.5
turns/min). In the lesioned animals (n 5 12), methamphetamine-induced rotation continued to beobserved 15 weeks following induction of the lesion.
This behavior was reversed by the intrastriatal graftin the 4th week after transplantation (7 weeks postlesion), and then continued throughout 12 weeks
post-grafting (main effect of groups, F1,32 5 33.75,
P < 0.01; main effect of time, F2,32 5 21.32, P <0.01; groups 3 time interaction, F2,32 5 25.59, P <0.01). Some of the grafted animals turned away fromthe grafted side in a contralateral direction (20.2 6
1.2 turns/min at 4 weeks and 21.3 6 0.9 turns/min
at 12 weeks post-grafting; n 5 6), which was considered to be a functional overcompensation in theirrotational behavior (Fig. 1).
Fos and Zif268 immunohistochemistry
In the saline-treated control animals, Fos-positive
cells were very sparse in all three regions observed:
the medial CPu, GP, and SNr (Fig. 3). In contrast,

FOS AND ZIF268 IN HEMIPARKINSONIAN RATS

923

Fig. 2. Fos expression 2 h after methamphetamine (3 mg/kg,
i.p.) administration in the basal ganglia nuclei of the control, thelesioned and the grafted rats ipsilateral to the lesion/graft (leftside). CPu, caudate putamen; GP, globus pallidus; SNr, substantia
nigra pars reticulata. The box in the drawing indicates the locationof areas where photomicrographs were taken. Scale bar 5 100 lm.

Zif268 was expressed in relatively high levels basallyin the medial CPu, but sparse in both the GP and theSNr (Fig. 5).
The administration of methamphetamine to the 6OHDA rats induced Fos expression in the medial CPu
and GP on both sides; the number of Fos-positive cells
was smaller on the lesioned side than on the intact
side especially in the GP (Fig. 3). In contrast, thenumber of Fos-positive cells in the SNr in the 6OHDA rats was greater on the lesioned side thanon the intact side. In the grafted rats, methamphetamine-induced FLI in the medial CPu on thelesion-grafted side was higher than that in the normal striatum of control animals. The decreased levelsof methamphetamine-induced FLI in the GP on thelesioned side were restored by the intrastriatal grafts.
However, the hyperexpression of FLI in the SNr on
the lesioned side was not altered by the intrastriatal
grafts (Figs. 2 and 3).
Methamphetamine induced a similar pattern ofZif268 expression in the medial CPu to that of Fos in
the three groups (control, lesion, graft) (Figs. 2 and
4). Regarding the GP and SNr, however, little Zif268
expression was observed on both sides in all threegroups even after the methamphetamine administration (Figs. 4 and 5).
DISCUSSION
Constitutive levels of Zif268 were seen in the striatum, where very low levels of Fos were observed, con-Fig. 3. Density of Fos-positive cells (number/0.25 mm2) as
detected within the medial CPu (top panel), GP (middle panel) andthe SNr (bottom panel) in saline-treated controls (n 5 6), methamphetamine (3 mg/kg, i.p.)-treated controls (n 5 6), methamphetamine-treated lesioned (n 5 6) and methamphetamine-treatedgrafted rats (n 5 6). METH, methamphetamine. The results are themeans 6 SEM. *P < 0.05, **P < 0.01 in comparison to each corresponding value of the methamphetamine-treated control rats (twoway ANOVA followed by Newman-Keuls test). ##P < 0.01 for themethamphetamine-treated graft group in comparison to each corresponding value of the methamphetamine-treated lesioned rats (twoway ANOVA followed by Newman-Keuls test). $$P < 0.01 in comparison to each value in the corresponding ipsilateral (left side) portion of
the same group (two-way ANOVA followed by Dunnett’s t-test).

sistent with that seen in previous studies (Ishida
et al., 2000; MacGibbon et al., 1995). Constitutively
expressed IEGs may perhaps be involved in controlSynapse

924

Y. ISHIDA ET AL.

Fig. 4. Zif268 expression 2 h after methamphetamine (3 mg/kg,
i.p.) administration in the basal ganglia nuclei of the control, thelesioned and the grafted rats ipsilateral to the lesion/graft (leftside). CPu, caudate putamen; GP, globus pallidus; SNr, substantia
nigra pars reticulata. The box in the drawing indicates the locationof areas where photomicrographs were taken. Scale bar 5 100 lm.

ling housekeeping genes stimulated by tonic messengers, such as glutamate through NMDA receptors(Ishida et al., 2000). The genes activated basally may
include those genes that sustain neuronal cell function and viability, while the novel messengers arriving at the cell surface, which rapidly and transiently
activate IEGs, work to modulate the transcriptional
activity of other genes that change the phenotype ofthe cell depending on the information carried by themessenger. Alternatively, perhaps the IEG proteinspresent basally are not active, and their activation
requires post-translational modiﬁcations (phosphorylation, demethylation, etc.) (Seyfert et al., 1990). A
previous report suggested that Zif268 may play a rolein spontaneously maintaining the inhibitory output of
GABAergic neurons in the striatum (Ishida et al.,2000).
Based on the results described previously (Ishida
et al., 1996; Schmidt et al., 1983), it appears that analmost complete loss of the DA content is achieved in
the denervated striatum in the 6-OHDA-treated rats
in the present study. Previous cerebral dialysis andimmunohistochemical studies have shown that basal
and methamphetamine-induced DA release wasrecovered and that an abundance of tyrosine hydroxylase-immunopositive cells and ﬁbers could beobserved in the lesion-grafted striatum in the grafted
rats in which methamphetamine-induced rotation
was completely ameliorated similarly in the present
study (Ishida et al., 1998a; Nishino et al., 1990).
SynapseFig. 5. Density of Zif268-positive cells (number/0.25 mm2) as
detected within the medial CPu (top panel), GP (middle panel) andthe SNr (bottom panel) in saline-treated controls (n 5 6), methamphetamine (3 mg/kg, i.p.)-treated controls (n 5 6), methamphetamine-treated lesioned (n 5 6) and methamphetamine-treatedgrafted rats (n 5 6). METH, methamphetamine. The results are themeans 6 SEM. **P < 0.01 in comparison to each corresponding
value of the methamphetamine-treated control rats (two-way
ANOVA followed by Newman-Keuls test). ##P < 0.01 for the methamphetamine-treated graft group in comparison to each corresponding value of the methamphetamine-treated lesioned rats (two-way
ANOVA followed by Newman-Keuls test).

A large increase in Fos and Zif268 levels wereobserved in the striatum after methamphetamine
administration, as observed in previous studies

FOS AND ZIF268 IN HEMIPARKINSONIAN RATS

(Moratalla et al., 1992; Wang et al., 1994). Similar tothe pattern of Fos activation, methamphetamineinduced Zif268 activation was lower in the lesioned
striatum and higher (although, not signiﬁcantly) in
the lesion-grafted striatum in comparison to that in
the control striatum. However, the drug-regulated
expression of these two genes is not identical: theatypical antipsychotic drug clozapine induces zif268
but not c-fos in the caudate-putamen (Nguyen et al.,1992). The differential regulation of c-fos and zif268
has been reported in the dentate gyrus of the hippocampus after the high-frequency stimulation of the perforant path (Cole et al., 1989). The similarity in the distribution of inducible expression suggests that althoughthese two IEGs may differ in their functions in quiescent neurons, they may have analogous or cooperativeroles in neuronal responses to methamphetamine in
the control, lesioned, or lesion-grafted striatum.
Similar to the results reported previously (Abrous
et al., 1992; Cenci et al., 1992), the present study
demonstrates that the stimulant effect of methamphetamine on Fos expression can be restored, andfurthermore, the density of methamphetamineinduced FLI within the grafted striatum is larger
than that observed within the normal striatum.
Abrous et al. have suggested (1992) that the exaggerated pharmacological response following intrastriatal
grafting of VM might be linked to an abnormal postsynaptic restitution of DA control over the activity oftarget striatal neurons. Although the lesion-induced
motor imbalance was ameliorated completely in thegrafted rats, the intrastriatal grafts had little inﬂuence on the methamphetamine-induced hyperexpression of FLI in the SNr on the lesioned side. Therefore,
the hyperexpression of nigral FLI could be induced
independently of the tuning behavior following methamphetamine administration.
The 6-OHDA lesion can lead to the depletion of DA,
not only in the striatum but also in the prefrontal
cortex, the subthalamic nucleus, and various otherlimbic targets, which may induce postsynaptic alterations in the DA receptor number and in the sensitivity of various receptor-linked biochemical events inthese areas (Campbell et al., 1985; Joyce, 1991;
Mishra et al., 1980). The postsynaptic alterations
remaining in the denervated areas except for the DAreinnervated striatum might explain the failure of
intrastriatal grafts to exert signiﬁcant effects on
methamphetamine-induced Fos activation in the SNron the lesioned side. It is suggested that the FLIs in
the two discrete sites, medial CPu and SNr, are activated independently by different mechanisms, andfurthermore, different neuronal pathways are involved in the methamphetamine-induced rotation and
Fos expression in the SNr of 6-OHDA rats.
Although the mechanism by which methamphetamine induces pallidal Fos is unclear, one possibility925

is that methamphetamine reduces striopallidal transmission through increased DA D2 receptor activation.
This notion is supported in a study by Floran et al.
(1997) which showed that methamphetamine or theD2 agonist, quinpirole, inhibits the release of GABA
in the GP of the rat. Also, Black et al. (1997) used
positron emission tomography (PET) in the baboon todemonstrate that cerebral blood ﬂow to the GP is
reduced signiﬁcantly after the intravenous administration of a D2-selective agonist.
In the 6-OHDA rats, a signiﬁcant difference in themethamphetamine-induced FLI between the lesioned
and the intact striata was present also in GP. The
side-to-side difference in GP seen in the 6-OHDA rats
was no longer present in the grafted animals. As
Cenci et al. reported previously (1992); fetal VM
transplants normalize DA receptor-mediated function
in a primary target of the striatal output neurons,
the GP, as well as in the 6-OHDA-lesioned striatum.
In contrast to the striatum, both of the GP and SNr
showed little Zif268 activation following methamphetamine challenge in rats of the three groups (control,
lesion, graft). It is noteworthy to mention that Zif268
immunoreactivity was not increased in parallel with
Fos following methamphetamine administration, indicating that the speciﬁc pattern of IEGs activation
upon stimulation of dopaminergic neurons seems to
be maintained in the basal ganglia.
In conclusion, the differential expression of Fos andZif268 was observed among three regions (medial
CPu, GP, SNr) of the nigrostriatal system following
methamphetamine in 6-OHDA-treated hemiparkinsonian rats, thus suggesting the presence of both genespeciﬁc and region-speciﬁc functions of Fos andZif268 in the basal ganglia nuclei. Further studies
are necessary to elucidate CNS functions of the IEGs
in diverse ways.
ACKNOWLEDGMENT
The authors thank Ms. Fumiko Tsuda for her excellent technical assistance.
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