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The Journal of Neuroscience, September 15, 2002, 22(18):8133-8138
 FosB Regulates Wheel Running
Martin
Werme1,
Chad
Messer3,
Lars
Olson1,
Lauren
Gilden3,
Peter
Thorén2,
Eric J.
Nestler3, and
Stefan
Brené1
Departments of 1 Neuroscience and
2 Physiology and Pharmacology, Karolinska Institutet,
Stockholm, S-171 77 Sweden, and 3 Department of Psychiatry
and Center for Basic Neuroscience, The University of Texas Southwestern
Medical Center, Dallas, Texas 75390-9070
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ABSTRACT |
 FosB is a transcription factor that accumulates in a
region-specific manner in the brain after chronic perturbations. For example, repeated administration of drugs of abuse increases levels of
FosB in the striatum. In the present study, we analyzed
the effect of spontaneous wheel running, as a model for a natural rewarding behavior, on levels of FosB in striatal
regions. Moreover, mice that inducibly overexpress FosB
in specific subpopulations of striatal neurons were used to study the
possible role of FosB on running behavior. Lewis rats
given ad libitum access to running wheels for 30 d
covered what would correspond to ~10 km/d and showed increased levels
of FosB in the nucleus accumbens compared with rats
exposed to locked running wheels. Mice that overexpress FosB selectively in striatal dynorphin-containing neurons
increased their daily running compared with control littermates,
whereas mice that overexpress FosB predominantly in
striatal enkephalin-containing neurons ran considerably less than
controls. Data from the present study demonstrate that like drugs of
abuse, voluntary running increases levels of FosB in
brain reward pathways. Furthermore, overexpression of
FosB in a distinct striatal output neuronal population
increases running behavior. Because previous work has shown that
FosB overexpression within this same neuronal population increases the rewarding properties of drugs of abuse, results of the
present study suggest that FosB may play a key role in controlling both natural and drug-induced reward.
Key words:
nucleus accumbens; striatum; locomotion; exercise; natural reward; behavioral addiction; compulsive; drugs of abuse
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INTRODUCTION |
FosB belongs to the
Fos family of transcription factors and is derived from the fosb
gene via alternative splicing. Unlike all other Fos-like
proteins, which have short half-lives, the 35 and 37 kDa isoforms of
FosB accumulate in a region-specific manner in the brain
after a variety of chronic perturbations, presumably because of the
very high stability of these isoforms (Hope et al., 1994a ; Chen et al.,
1997; Nestler et al., 1999). The regulation of FosB in
striatal regions after repeated administration of drugs of abuse has
been especially well studied (Hope et al., 1994b; Moratalla et al.,
1996; Chen et al., 1997; Nestler et al., 1999). The mesolimbic dopamine
pathway has a central role in drug reward (Koob et al., 1998). It
originates in the ventral tegmental area of the midbrain and terminates
in the ventral part of the striatum, called the nucleus accumbens.
Acute administration of any of several drugs of abuse transiently
induces several Fos family proteins in the nucleus accumbens and in the
dorsal striatum. These proteins form heterodimers with Jun family
proteins to form activator protein-1 (AP-1) transcription factor
complexes with short half-lives. In contrast, after repeated drug
treatment, induction of these immediate early gene products declines
and, instead, there is a gradual accumulation of the stable
FosB isoforms. FosB heterodimerizes
predominantly with JunD and to a lesser extent with JunB (Hiroi et al.,
1998; Perez-Otano et al., 1998) to form long-lasting AP-1 complexes in
specific brain regions. It has been proposed that these long-lasting
AP-1 complexes mediate some of the long-term effects of drugs of abuse
on brain reward pathways that underlie addiction (Nestler et al.,
2001).
Behavioral studies suggest that wheel running in rodents is rewarding.
This assumption is based on experiments showing that rats lever-press
for access to running wheels and also develop conditioned place
preference to an environment associated with the aftereffects of wheel
running (Iversen, 1993; Belke, 1997; Lett et al., 2000). Moreover, rats
that run long distances daily exhibit withdrawal signs, such as
increased aggression, when access to the running wheels is denied
(Hoffmann et al., 1987). Surveys among highly committed human runners
suggest that running is an addictive behavior for many individuals
(Rudy and Estok, 1989; Chapman and De Castro, 1990; Furst and Germone,
1993). Indeed, running displays many of the criteria included in the
Diagnostic Statistical Manual (American Psychiatric Association,
1994) for the diagnosis of addiction.
The goal of the present study was to investigate whether levels
of FosB are altered by a natural rewarding behavior such as running and whether inducible overexpression of FosB
in striatal regions might regulate running behavior. We show here that,
like drugs of abuse, chronic running induces FosB in the
nucleus accumbens; in addition, the overexpression of
FosB in the two different subsets of striatal projection
neurons has opposite effects on wheel running. The data reveal striking
similarities between addictive drugs and wheel running and suggest an
important role for FosB in regulating both natural and
drug-induced rewards.
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MATERIALS AND METHODS |
Animals. Male Lewis rats (Møllegaard Breeding
Center, Skansved, Denmark) weighing 250 gm at the onset of the
experiment were used. The rats had access ad libitum to
water, food, and running wheels. They were on a 12 hr light/dark cycle,
with lights on at 10 A.M. and lights off at 10 P.M. Cages (43 × 22 × 20 cm) contained a running wheel with a diameter of 34 cm;
hence, one revolution corresponds to 1.07 m. After 4 weeks of
voluntary wheel running, the rats were killed by decapitation, and
tissues were taken for Western blotting or perfused with fixative and
processed for immunohistochemistry and in situ hybridization.
Two lines of bitransgenic mice that can inducibly overexpress
FosB selectively in striatal regions under the control of
the tetracycline gene regulation system were also used (Chen et al., 1998). In one line, called 11A, FosB is inducibly
overexpressed solely in striatal projection neurons that express the
neuropeptide dynorphin after removal of doxycycline (Kelz et al.,
1999). In the other line, called 11B, FosB is inducibly
overexpressed predominantly in striatal projection neurons that express
the neuropeptide enkephalin after removal of doxycycline, although some
expression is seen in dynorphin neurons as well. Controls and
FosB-overexpressing mice are littermates within each line
(11A and 11B) and have the same bitransgenic construct, which can be
activated by removal of doxycycline. All mice were conceived and raised
on the tetracycline derivative doxycycline at a dose of 100 µg/ml in
the drinking water. As adults, one-half of the resulting litters were
maintained on doxycycline (controls); the other half were removed from
doxycycline (FosB overexpressers) for the rest of the
experiment. Six weeks after removal of doxycycline, at which time
FosB expression is known to be maximal (Chen et al.,
1998; Kelz et al., 1999), the running wheels were unlocked for both
mice on tetracycline (controls) and mice on tap water
(FosB overexpressers), and voluntary running started. To
rule out the possibility that doxycycline itself affected wheel-running
behavior, we analyzed wheel running in C57BL/6 mice (Charles River,
Uppsala, Sweden) treated with 100 µg/ml doxycycline for 6 weeks
before being allowed access to the running wheels. The mice were then
placed in the cages with ad libitum access to the running
wheels and remained on tetracycline during the entire experiment. The
control group received normal drinking water during the entire
experiment. Mouse cages (22 × 16 × 14 cm) contained a
running wheel with a diameter of 12.4 cm; hence, one revolution
corresponds to 0.39 m. Running data from both rats and mice were
sampled every 30 min using customized computer software.
Western blotting. Brains were removed rapidly from
decapitated rats and chilled in ice-cold physiological buffer. Punches with a diameter of 2 mm were used to sample tissues from the nucleus accumbens and the medial and lateral caudate putamen in 1-mm-thick coronal slices of brain at the level of bregma 0.7-1.7 mm (Paxinos and
Watson, 1997). Brain samples were homogenized in 1% SDS, and protein
determinations were made using the method of Lowry. Homogenates containing between 5 and 50 µg of protein were loaded onto
SDS-polyacrylamide gels and subjected to electrophoresis as described.
A rabbit anti-Fos antibody (1:4000; M. J. Iadarola, National
Institutes of Health, Bethesda, MD) or anti-FosB (N-terminal) antibody
(1:4000; Santa Cruz Biotechnology, Santa Cruz, CA) was used for
detection of FosB. Proteins were detected using
horseradish peroxidase-conjugated IgG antibodies (1:2000; Vector
Laboratories, Burlingame, CA) followed by chemiluminescence (DuPont
NEN, Boston, MA). Levels of immunoreactivity (IR) were quantified on a
Macintosh-based image analysis system, and levels of protein in the
experimental samples were compared with those of controls. Blots were
stained by amido black to confirm equal loading and transfer of the
gels. Blots were also immunolabeled for 68 kDa neurofilament protein,
which did not show differences between the experimental and control
groups (data not shown).
Immunohistochemistry. Lewis rats that had run for 4 weeks
and controls with locked wheels were deeply anesthetized with
pentobarbital and perfused intracardially with 50 ml of
Ca2+-free Tyrode's solution (room
temperature) including 0.1 ml of heparin. This was followed by 250 ml
of fixative (4% paraformaldehyde and 0.4% picric acid in 0.16 M PBS, pH 7.4, at room temperature). Brains were
divided and kept in fixative for 1 hr and subsequently rinsed in 0.1 M PBS with 10% sucrose and 0.1% sodium azide
several times over 24 hr at 4°C for cryoprotection. The brains were
frozen, and 14 µm coronal sections were collected at levels ranging
between bregma 0.70 and 1.70 mm. Sections were rinsed three times for 10 min in PBS before overnight incubation (4°C in moisture chamber) with primary polyclonal anti-FosB (N-terminal) antibody (1:500; Santa Cruz Biotechnology) in 0.3% Triton-PBS (150 µl per section). This was followed by three rinses with PBS for 10 min before incubation for 1 hr at room temperature with the secondary biotinylated
anti-rabbit IgG antibody (1:200; Vector Laboratories) in 0.3%
Triton-PBS (150 µl per section). Another three rinses in PBS for 10 min were performed before the avidin-biotin complex was added (1:100
and 1:100, respectively, in 0.1 M PBS; 150 µl
per section). After three 10 min rinses, the complex was visualized
after a 7 min incubation with the substrate according to the
manufacturer's protocol (Vector Laboratories). Sections were
subsequently rinsed three times for 5 min.
In situ hybridization. For combined immunohistochemistry and
in situ hybridization experiments, brain sections that had
been processed for immunohistochemistry were immediately subjected to
in situ hybridization, which was performed essentially as
described previously (Seroogy et al., 1989; Dagerlind et al., 1992).
Forty-eight mer DNA oligonucleotide probes specific for dynorphin
(296-345) (Douglass et al., 1989) and enkephalin (235-282) (Zurawski
et al., 1986) mRNAs were radioactively labeled with
[ -35S]dATP (DuPont NEN) in their 3'
ends using terminal deoxynucleotidyl transferase (Invitrogen, San
Diego, CA) to a specific activity of ~1 × 109 cpm/mg. The hybridization cocktail
contained 50% formamide, 4× SSC (1× SSC is 0.15 M NaCl and 0.015 sodium citrate, pH 7.0), 1×
Denhardt's solution, 1% sarcosyl, 0.02 M
Na3PO4, pH 7.0, 10% dextran sulfate, 0.06 M dithiothreitol, and 0.1 mg/ml sheared salmon sperm DNA. Hybridization was performed for 18 hr
in a humidified chamber at 42°C. After hybridization, the sections
were rinsed four times for 20 min each in 1× SSC at 60°C.
Thereafter, the sections were rinsed in autoclaved water for 10 sec,
dehydrated in alcohol, and air-dried. Finally, NTB2 nuclear
track emulsion (diluted 1:1 with water; Kodak, Rochester, NY) was
applied by dipping. After 2-4 weeks of exposure, the slides were
developed with D19 (Kodak) and fixed with Unifix (Kodak).
Counts of cells positive for FosB-IR and cells
colocalizing FosB-IR and dynorphin mRNA or enkephalin mRNA in rats
after 4 weeks of running (n = 8) and in controls
(n = 8) were performed on one slide per animal by an
independent observer blinded to the experimental design. Analysis was
performed at the level of bregma 1.2 mm (Paxinos and Watson, 1997).
Statistical procedures. To analyze the difference in
FosB levels between controls and runners in the Western
blotting and immunohistochemistry experiments, t tests were
performed. The effect of overexpression of FosB on
running behavior in the transgenic mice was analyzed using a two-way
ANOVA with repeated measurements, analyzing within-group and
between-group effects (Statistica version 99; StatSoft, Tulsa, OK).
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RESULTS |
Regulation of FosB in nucleus accumbens by wheel
running
Lewis rats placed in cages with running wheels increased their
amount of daily running linearly until day 13, when they stabilized at
10.210 ± 590 m/d (mean ± SEM). This level was roughly
maintained through day 32, when the animals were used for biochemical
analysis. During the last 4 d, the rats ran 8.910 ± 900 m/d.
This running behavior in Lewis rats is similar to that observed
previously (Werme et al., 1999). Subsequently, levels of
FosB were analyzed by Western blotting in the nucleus
accumbens and in the medial and lateral caudate putamen in running
(n = 7) and control (n = 7) rats. As
shown in Figure 1, wheel running
increased FosB levels of the 37 and 35 kDa isoforms in
the nucleus accumbens (p < 0.05). In contrast,
there was no difference in FosB levels between runners
and controls in the medial or lateral caudate putamen (data not
shown).
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Figure 1.
Regulation of FosB by wheel running.
Levels of the 35-37 kDa isoforms of FosB were measured
in the nucleus accumbens using Western blotting in control rats
(C) and in rats that underwent 4 weeks of
voluntary wheel running (R). Top,
Representative lanes from the blots. Data are expressed
as mean ± SEM (both groups, n = 7).
*p < 0.05.
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Immunohistochemistry revealed the presence of
FosB-positive cells in the nucleus accumbens of control
(n = 8) and running (n = 8) rats.
Counts of FosB-positive cells in the core and shell revealed an increase in the number of cells expressing
FosB-IR in the core (p < 0.05)
but not in the shell of nucleus accumbens after running (Fig.
2). Combined immunohistochemistry for
FosB-IR and in situ hybridization for
enkephalin or dynorphin mRNA in the nucleus accumbens was subsequently
used to identify the cell type within this brain region in which
FosB is induced by running (Fig.
3). While the number of cells expressing
both dynorphin mRNA and FosB-IR was higher in runners
(n = 8) than in controls (n = 8) (Table
1), the mean number of cells expressing
both enkephalin mRNA and FosB-IR in runners was lower than in
controls (Table 1). These effects were apparent in the core subdivision
of this brain region (Table 1). These results indicate that the
induction of FosB by running occurs predominantly in the
dynorphin-containing subset of nucleus accumbens neurons.
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Figure 2.
Wheel running affects the number of
FosB-positive cells in the nucleus accumbens.
Top, Representative photomicrographs of rat brain
sections demonstrating the increase in the number of
FosB-positive cells in the nucleus accumbens core when
runners (Run) were compared with controls
(Ctr). aca, Anterior commissure anterior.
Bottom, Bar graph of counts of cells positive for
FosB-IR in the medial aspects of the core and shell of
the nucleus accumbens in control rats and in rats that underwent 4 weeks of voluntary wheel running. Data are expressed as mean ± SEM (both groups, n = 8). *p < 0.05.
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Figure 3.
Cellular specificity of FosB
induction by wheel running. Representative photomicrographs of rat
brain sections from eight individuals demonstrating colocalization of
FosB-IR (brown stained nuclei) and
dynorphin mRNA (black grains) (a)
or FosB-IR and enkephalin mRNA in the nucleus accumbens
core (b).
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Effect of FosB on wheel running
To study a possible role of FosB in regulating wheel
running, we used two lines of bitransgenic mice that inducibly
overexpress FosB within striatal regions of adult animals
(Chen et al., 1998; Kelz et al., 1999). The bitransgenic 11A line can
inducibly overexpress FosB solely within
dynorphin-containing neurons in the striatum (Kelz et al., 1999),
whereas the bitransgenic 11B line can inducibly overexpress
FosB predominantly in enkephalin-containing neurons in
this region, with some expression seen in dynorphin neurons as well
(Fig. 4). Both lines of mice were
conceived and raised on doxycycline to keep FosB
expression turned off (Fig. 4) (Kelz et al., 1999), and one-half of the
littermates were removed from doxycycline as adults to turn on
FosB expression.
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Figure 4.
Expression of FosB in 11B mice.
Brain sections were analyzed for FosB-IR
(brown-stained nuclei) followed by in
situ hybridization for dynorphin mRNA (A)
or enkephalin mRNA (B) (black
grains). Note the preferential expression of
FosB-IR in the enkephalin-positive but not the
dynorphin-positive cells. Of 214 FosB-positive cells
counted in three 11B mice, 73 ± 11% were also enkephalin
positive, and 22 ± 6% were also dynorphin positive. No
double-labeling was seen between FosB and interneuron
markers.
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11A mice that overexpress FosB (no doxycycline)
(n = 7) were found to increase their daily running
distance over the first 3 weeks compared with the littermate controls
(given doxycycline) (n = 8), which showed a
plateau in their rate of running after 2 weeks (Fig.
5A). In striking contrast, 11B
mice that overexpressed FosB (n = 7)
showed considerably less running activity during weeks 2 and 3 than
their littermate controls (n = 6) (Fig. 5B). To investigate the possibility that doxycycline itself might alter running behavior, we compared wheel running of C57BL/6 mice with and
without doxycycline in their drinking water. No difference between the
groups was found (data not shown).
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Figure 5.
Effect of FosB overexpression on
wheel running behavior in bitransgenic mice. A,
Bitransgenic mice drinking tap water have inducible overexpression of
FosB in striatal dynorphin neurons (water)
and showed increased running (distance per day) for the first 3 weeks
of access to running wheels. In contrast, genetically identical
littermate controls with doxycycline in their drinking water that do
not overexpress FosB (dox) showed
increased running for the first 2 weeks only. B, Another
line of the bitransgenic strain of mice, called 11B, with inducible
overexpression of FosB primarily in striatal enkephalin
neurons (water) showed dramatically less running during
their weeks 2 and 3 compared with genetically identical littermates
that do not overexpress FosB (dox). # indicates an increase in running (distance per week) within a group.
* indicates a difference in running between the FosB
overexpressers (water) and controls
(dox). Vertical lines indicate borders
between weeks 1 and 2, as well as weeks 2 and 3. Horizontal
lines with the # symbol describe statistical differences between
weekly running within a group. Data are expressed as mean (11A dox,
n = 8; 11A water, n = 7; 11B
dox, n = 6; 11B water, n = 7).
#p < 0.05;
##p < 0.01;
###p < 0.001; *p < 0.05.
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DISCUSSION |
In this study, we show that like repeated exposure to drugs of
abuse, chronic wheel running, a natural rewarding behavior, induces
FosB in the nucleus accumbens, a critical part of the reward pathways of the brain. We also show that overexpression of
FosB in striatal dynorphin neurons of adult animals
increases running behavior, whereas FosB expression
primarily in striatal enkephalin neurons has the opposite effect. These
data support the view that FosB is critically involved in
long-term effects of natural and drug-induced rewards and underscore
the important role of FosB in the regulation of striatal function.
Similar molecular responses to drugs of abuse and running
Drugs of abuse as diverse as psychostimulants, opiates, alcohol,
nicotine, and phencyclidine increase levels of FosB in
the nucleus accumbens (Hope et al., 1994b; Nye et al., 1995; Nye and Nestler, 1996; Nestler et al., 1999), and here we show that chronic running behavior results in a similar response. Chronic cocaine and
running induce additional common adaptations, for example, induction of
dynorphin mRNA in certain regions of the striatum (Werme et al., 2000).
As noted previously for cocaine (Hiroi et al., 1997), the induction of
FosB by running is stronger in the core than in the shell
division of the nucleus accumbens. However, FosB
induction by running is restricted to the nucleus accumbens, whereas
drugs of abuse induce the protein in the caudate putamen as well.
Previous studies have demonstrated that FosB is expressed solely in projection neurons of the striatum, and that chronic cocaine
increases FosB preferentially in the subpopulation of projection neurons that express dynorphin (Moratalla et al., 1996). In the present study, by use of combined immunohistochemistry and
in situ hybridization on the same tissue sections, we showed that wheel running also induces FosB preferentially
within dynorphin neurons.
The finding that drug reward and a natural reward induce the same
molecular adaptation (induction of FosB) within the same neuronal cell type suggests that the two may act via some common mechanism. One plausible common mechanism is increased dopaminergic transmission to the nucleus accumbens. Running and acute
administration of addictive drugs increases extracellular levels of
dopamine in this brain region (Freed and Yamamoto, 1985; Di Chiara and Imperato, 1988; Wilson and Marsden, 1995). Repeated treatment with the
D1 dopamine receptor agonist
(+/ )-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin hydrobromide alone or in combination with the
D2 receptor agonist quinpirole will increase
levels of FosB in the nucleus accumbens and dorsal
striatum (Nye et al., 1995). Psychostimulant addictive drugs such as
cocaine and amphetamine, which are indirect dopamine agonists, also
increase FosB levels in striatal regions (Jaber et al.,
1995; Nye et al., 1995). In addition, chronic administration of the
specific dopamine transporter antagonist
1-[2-(bis[4-fluorophenyl]methoxy)ethyl]-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate, but not of serotonin- or
norepinephrine-selective transporter inhibitors, induces
FosB in these brain regions (Nye et al., 1995). These
findings demonstrate that induction of FosB in the
striatum after various treatments is dependent on dopamine.
Opposite effects of FosB overexpression in striatal
dynorphin versus enkephalin neurons on wheel-running behavior
The bitransgenic mice with FosB overexpression that
is induced by doxycycline removal from adult animals show no overt
developmental abnormalities. In mice in which FosB
overexpression is selective for striatal dynorphin neurons, running
behavior increased during the first 3 weeks of running, instead of the
first 2 weeks as seen for control littermates. In marked contrast, mice
overexpressing FosB primarily in striatal enkephalin
neurons ran less than their control littermates during weeks 2 and 3 of
running. Interestingly, the two lines of bitransgenic mice studied here
also show different behavioral responses to drugs of abuse. Whereas
overexpression of FosB in dynorphin neurons increases the
rewarding effects of cocaine and morphine (Kelz et al., 1999; Nestler
et al., 2001), overexpression of FosB primarily in the
enkephalin neurons does not alter the rewarding effects of these drugs.
The opposite effects on running behavior seen in the two lines of mice
could be explained by the differential circuitry of these two distinct
subpopulations of striatal neurons. More than 90% of striatal neurons
are medium spiny projection neurons that use GABA as a
neurotransmitter. Approximately one-half of these neurons also express
high levels of dynorphin and substance P (and to a certain extent the
D1 dopamine receptor) (Gerfen et al., 1990; Le
Moine et al., 1991) and project directly to the midbrain. The other
half express high levels of enkephalin (and D2
dopamine receptor) (Gerfen et al., 1990; Le Moine et al., 1990) and
project indirectly to the midbrain via the globus pallidus and
subthalamic nucleus. Activation of the direct pathway increases locomotion, whereas activation of the indirect pathway decreases locomotion. Thus, the reciprocal changes in running behavior exhibited by the two lines of FosB-overexpressing mice used in
these experiments could reflect FosB-induced changes in
the excitability of the direct versus the indirect pathway. Along these
lines, it is interesting to speculate that the reduction in wheel
running seen in mice overexpressing FosB primarily in
enkephalin neurons may be consistent with the fact that
first-generation antipsychotic drugs, which decrease locomotor
activity, induce FosB selectively within this neuronal
subpopulation (Hiroi and Graybiel, 1996; Atkins et al., 1999).
Target genes regulated by FosB
The effects of FosB on neuronal function are
presumably mediated via the regulation of other genes. Given that many
genes contain consensus sites for AP-1 complexes in their promoter
regions, it is likely that the actions of FosB on neurons
involve complex effects on numerous genes. Only a few have been
identified to date. The AMPA glutamate receptor subunit 2 (GluR2) is
upregulated by FosB in the nucleus accumbens, an effect
not seen in the dorsal striatum (Kelz et al., 1999). Cyclin-dependent
kinase 5 (Cdk5) is upregulated in both the nucleus accumbens and dorsal
striatum (Bibb et al., 2001). These effects could be mediated via AP-1 sites present in the promoter regions of these genes (Brene et al.,
2000; Chen et al., 2000). Regulation of GluR2 would be expected to
alter the electrical excitability of striatal neurons by changing their
AMPA receptor sensitivity. Regulation of Cdk5 might also alter the
excitability of these neurons through a pathway involving dopamine and
cAMP-regulated phosphoprotein-32, which is highly enriched in
striatal medium spiny neurons (Brene et al., 1994; Bibb et al., 1999).
However, further work is needed to identify the precise molecular
pathways by which FosB, through changes in the expression
of other genes, alters the functional state of striatal dynorphin and
enkephalin neurons.
Conclusions
The findings that similar molecular adaptations occur in the
nucleus accumbens in natural and drug-induced reward situations suggest
that common neurobiological mechanisms may control both types of
rewarding behaviors. One core similarity between these behaviors is
their addictive nature. FosB is induced by both behaviors
and enhances both behaviors when independently overexpressed in
striatal dynorphin neurons. Perhaps FosB, when expressed
in these neurons, sensitizes a neural circuit related to compulsive behavior. Although speculative, the increasing knowledge about FosB suggests that it, or the various molecular pathways
it regulates, could be a suitable target for the development of
pharmacological treatments for a range of disorders. Examples of these
could be compulsive behaviors, including not only drug addiction but
also eating disorders, pathological gambling, excessive exercise, and perhaps even obsessive-compulsive disorder.
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FOOTNOTES |
Received Jan. 29, 2002; revised June 11, 2002; accepted June 12, 2002.
This work was supported by the Swedish Research Council (03185, 11642, and 04762), the Centrum för idrottsforskning (CIF 86/01),
the National Institute on Drug Abuse, and the National Institute on
Aging. We thank Karin Pernold and Karin Lundströmer for excellent
technical assistance.
Correspondence should be addressed to Stefan Brené, Department of
Neuroscience, Karolinska Institutet, Stockholm, S-171 77 Sweden.
E-mail: stefan.brene{at}neuro.ki.se.
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