Behavioural Brain Research 190 (2008) 212–217
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Behavioural Brain Research
journal homepage: www.elsevier.com/locate/bbr
Role of fosB in behaviours related to morphine reward and spatial memory
Wojciech Soleckia, Tomasz Krowkaa, Jakub Kubika, Leszek Kaczmarekc, Ryszard Przewlockia,b,∗
aDepartment of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Science, 12 Smetna Street, 31-343 Krakow, Poland
bDepartment of Neurobiology, Institute of Applied Psychology, Jagiellonian University, 19 Jozef Street, 31-056 Krakow, Poland
cDepartment of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland
a r t i c l e i n f o
Received 13 February 2008
Accepted 28 February 2008
Available online 6 March 2008
Immediate early gene
a b s t r a c t
The immediate early genes (IEGs) have been suggested to be implicated in mechanisms of addiction, as
impact on response to psychoactive drugs, as well as motivational and stress-related behaviours. In the
present study, we used mice with constitutive knock-out of fosB in order to study fosB role in mouse
phenotype. We studied rewarding properties of morphine (10mg/kg i.p.) in conditioned place preference
(CPP) paradigm. Additionally, we studied fosB role in spatial memory and spatial working memory using
elevated plus maze model of spatial learning (EPMSL) and delayed non-match to place task (DNMTP). In
of morphine in fosB −/− mice were abolished whereas spatial learning was impaired. On the other hand,
we found no significant differences in locomotor activity, depression-like and anxiety-like behaviours. In
and display spatial memory impairment and suggest involvement of fosB and its proteins in motivational
aspects of reinforcers as well as in learning and memory processes.
© 2008 Elsevier B.V. All rights reserved.
The fos family of immediate early genes (IEGs) has been pro-
posed to underlay adaptive neural responses, playing an important
role in drug-induced neuroplasticity [15,27,29] as well as memory
fosB, fra-1, and fra-2 .
mediating molecular responses in neurons with long-lasting phe-
notypical effects . It has been shown that lack of fosB in mice
has an influence on the nurturing behaviour  as well as nicotine,
cocaine and stress-related behaviours [17,45].
fosB gene gives rise to both a full-length protein (FosB) and
a truncated form called delta FosB, derived from an alternatively
spliced mRNA . For many years, delta FosB has drawn special
sistence of delta FosB even in the absence of additional stimulation
distinguishes it from all other fos family transcription factors.
It has been established that delta FosB is induced to high lev-
els in a region-specific manner in the brain after chronic exposure
∗Corresponding author at: Department of Molecular Neuropharmacology, Insti-
tute of Pharmacology, Polish Academy of Science, 12 Smetna Street, 31-343 Krakow,
Poland. Tel.: +48 12 66 23 218; fax: +4812 63 74 500.
E-mail address: email@example.com (R. Przewlocki).
to drugs of abuse and natural rewards, but also to a variety of
psychoactive stimuli, such as stress, certain lesions, antipsychotic
reported that elevated striatal levels of delta FosB increase sensi-
tivity of mice to rewarding properties of cocaine and morphine in
conditioned place preference paradigm [23,44]. Moreover, it has
been shown that striatal delta FosB overexpression can enhance
motivation to self-administer cocaine in mice .
Olausson et al.  has hypothesized that delta FosB may act
as a general molecular switch associated with enhancements in
the motivational aspects of reinforcers on goal-directed behaviour,
where its induction in NAc by addictive drugs, stress, or perhaps
highly rewarding foods, may be a mechanism by which dysfunc-
tional motivational states result in psychiatric disorders associated
with compulsive behaviour.
As shown above, several lines of evidence point to the fosB
role in rewarding properties of drugs of abuse as well as in link-
ing motivational states with behaviour. However, in animal models
measuring sensitivity to drug-induced reward (such as CPP or
self-administration paradigms) other phenotypic traits (such as
In the present study, we tested effects of constitutive knock-out
conditioned place preference paradigm. In addition, we tested the
role of fosB in spatial memory, locomotor activity, depression-like
and anxiety-like behaviours.
0166-4328/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
W. Solecki et al. / Behavioural Brain Research 190 (2008) 212–217
Our results indicate that rewarding properties of morphine are
abolished in fosB knock-out mice. However, we also report spatial
memory impairment with intact locomotor activity, depression-
like and anxiety-like behaviours in fosB knock-out mice.
2. Material and methods
Male fosB knock-out (−/−), and wild-type (+/+) age and litter matched mice
(25–30g) were housed under standard laboratory conditions. The subjects had free
bred into 129SvxBALB/c background mice in the Nencki Institute Animal House, as
described in more detail in paper of Korkosz et al. . Genotypes of all animals
were verified in each generation. All experiments were conducted during the light
phase (8:00–20:00h, lights on 8:00 a.m.) and complied with the NIH Guide for
the Care and Use of Laboratory Animals and were approved by the Local Bioethics
Committee (Krakow, Poland). All mice used in experiments were experimentally
na¨ ıve except for mice used in EPMSL which had been previously (1 week earlier)
tested in CPP. Experimenters were blind to the effects of mice genotype or drug
treatment in applied procedures.
2.2. Morphine conditioned place preference
Conditioned place preference was performed according to an unbiased proce-
dure, as described in paper by Popik and Wrobel . Briefly, we used Plexiglas
apparatus consisting of three rectangular arms (30cm×15cm×20cm) that dif-
fered in distinctive visual, tactile, and olfactory cues and triangular central platform.
Twenty-four hours before testing all mice were transferred into the testing room,
where they were weighed and handled. The conditioned place preference consisted
of three stages: preconditioning test (day 1), conditioning (days 2–7; morphine or
saline conditioning on day 2, 4, 6 and saline conditioning on day 3, 5, 7) and post-
conditioning test (day 8). During the preconditioning and postconditioning tests,
mice were placed individually on the central platform of the apparatus and had free
access to all three arms for 20min. The time spent in each arm as well as the num-
ber of arm entries (a raw measure of locomotor activity) were collected with use of
treatment groups (morphine+saline or saline+saline) were treated with morphine
2.3. Spatial memory in the elevated plus maze model of spatial learning
Spatial memory in elevated plus maze model of spatial learning was evaluated
in the elevated plus maze as described by Itoh et al. [20,21]. The maze was made of
black Plexiglas with a central platform (5cm×5cm), two open (5cm×30cm; illu-
minated −1000lux) and two closed (5cm×30cm ×15cm; illuminated −16lux)
arms elevated to a height of 50cm above the floor. In such test situation, mice
have strong anxiogenic motivation to find a “safe” closed arm. Twenty-four hours
before testing all mice were carried into the testing room, where they were han-
dled. On the test day, mice were individually placed at the end of the open arm
facing away from the central platform and the time it took for each mouse to move
from the open arm to either closed arm (transfer latency, TL) was recorded. TL was
defined as the time the animal took to enter the closed arm. Twenty-four hours
later, the second test was carried out during which mice were again put into the
open arm and the TL was again recorded. If the mouse did not enter the closed
arm within 90s on the first trial, it was carefully guided to the closed arm by the
experimenter. If the mouse did not enter the closed arm within 90s on the second
trial, the TL was assigned to 90s. The apparatus was cleaned and dried after each
2.4. Spatial working memory in the T-maze test
as described in the paper by Wietrzych et al.  using black Plexiglas T maze appa-
ratus with a runway arm of 50cm in length, each choice arm of 40cm length, and all
arms 10cm wide with walls 20cm in height. There was a square starting platform
(10cm×10cm) at the beginning of the runway arm and food cups were located at
the terminal end of each choice arm. The chocolate cereal served as reinforcement.
The animals received 14 days of training, five trials per day. Each trial consisted of a
sample run and a choice run beginning in a closed starting platform. On the sample
run, the mice were forced to enter either left or right arm to obtain a cereal reward,
by a Plexiglas slide door blocking the opposite arm. The door was then removed and
the mouse was placed at the starting platform and allowed a free choice of either
the last day when it was 20s. The mouse was rewarded for choosing the previously
unvisited arm (i.e., for alternating) by allowing chocolate cereal consumption.
2.5. Locomotor activity
Twenty-four hours before the locomotor activity test, the animals were habit-
uated to the room were actometers were placed. On the test day, mice were
individually placed in a centre of the cage (20cm×10cm×12cm) in which pho-
tocells recorded number of beam interruptions in horizontal plane, for each
15min, during a 2-h period. Horizontal movement was counted as locomotor activ-
2.6. Depressive-like behaviours in the forced swimming test
To study the depressive-like behaviours, we conducted forced swimming test
as described by Porsolt et al. . Mice were dropped individually into glass cylin-
der (height, 25cm; diameter, 10cm) containing 10–13.5cm of water, maintained at
23◦C, and were left there for 6min. The duration of immobility was recorded for the
last 4min of the 6-min testing period.
2.7. Anxiety-like behaviours in the four-plate test
To study anxiety-like behaviours, we performed the four-plate test as described
exploration of the novel environment is inhibited by the delivery of a mild electric
foot shock. The four-plate test was conducted in the box with floor covered with
four rectangular metal plates (11cm×8cm) separated by a gap of 4mm. The plates
were connected to a source of continuous current which enabled a 120V potential
difference between two adjacent plates for 0.5s when the experimenter pressed
a switch. Each mouse was gently placed in the middle of the apparatus and was
allowed to explore it. After 15s of free exploration, each time a mouse crossed from
one plate to another, the experimenter electrified the whole floor which evoked a
flight reaction of the animal. If the animal continued running, it received no new
shocks for the following 3s. The number of punished crossings were counted for
Polfa, Kutno) and injected interperitoneally (i.p.) in a volume of 0.1ml/10g of body
2.9. Statistical analysis
Data form CPP study are expressed as a difference (delta) between time spent in
rewarded arm in preconditioning test and time spent in the same arm in post-
conditioning test, and were analyzed by a one-way ANOVA with Newman–Keuls
post-hoc comparison. To study effects of genotype and training session in the T-
maze test, we used a two-way ANOVA with repeated measures. Similarly, to study
the effect of fosB knock-out on locomotor activity, we employed a two-way ANOVA
with repeated measures, with genotype, time and interaction factors. Bonferroni
3.1. Morphine rewarding properties measured in conditioned
Effects of fosB mutation in the conditioned place preference
test are shown in Fig. 1. Morphine (10mg/kg, i.p.) conditioning
in the drug-paired arm produced a significant preference of this
compartment in fosB +/+ mice but not in −/− mice [F(3,21)=3.95,
p<0.05]. Complementarily, saline conditioning on the drug-paired
side did not produced place preference in any tested group of
mice. In fosB +/+ mice, difference between (delta) time spent
on morphine-paired side in preconditioning and postconditioning
saline-paired side (−7.25±21.1s), as revealed by Newman–Keuls
post-hoc analysis (p<0.05). In fosB −/− mice, delta time spent in
morphine-paired compartment (−1.1±20.3s) was similar to delta
time spent in saline-paired compartment (−9.7±29s) however,
statistical analysis revealed significant difference when compared
to delta time spent in morphine-paired compartment of fosB +/+
W. Solecki et al. / Behavioural Brain Research 190 (2008) 212–217
Fig. 1. Morphine (10mg/kg, i.p.) conditioned place preference (CPP) in male fosB
wild-type (+/+; saline n=4, morphine n=8) and knock-out (−/−; saline n=4,
morphine n=8) mice. CPP data are expressed as the mean (±S.E.M.) delta time
spent on the drug-paired side between post-test and pre-test. *p<0.05 versus fosB
+/+ saline group,##p<0.01 versus fosB −/− morphine group; one-way ANOVA;
Newman–Keuls post-hock test.
3.2. Spatial memory in the elevated plus maze model of spatial
Results of fosB mutation in the elevated plus maze model of
spatial learning is shown in Fig. 2. Delta transfer latency between
first and second trial in the elevated plus maze model of spatial
learning of fosB −/− mice (12.64±5s; n=17) were shorter than
delta transfer latency in +/+ (43.5±8.4s; n=8) mice. The unpaired
Student’s t-test analysis of delta transfer latency revealed a signif-
icant differences (t=3, d.f.=23 p<0.005) between fosB −/− versus
+/+ mice. fosB −/− mice in the first test did not differ in transfer
latency (65.3±11.5s) in comparison to +/+ (61.7±7.8s) mice (data
3.3. Spatial working memory in the T-maze test
Effects of fosB mutation on the performance in the delayed non-
matched to place task in the T-maze test in fosB −/− (n=14), and
+/+ (n=16) mice during 13 days of training is shown in Fig. 3. The 5-
s interval between the acquisition, “forced run”, and the retention,
“choice run”, was sufficient to reveal the main effect of genotype
[F(1,336)=58.58, p<0.0001] and day [F(12,336)=15.01, p<0.0001],
however, no significant interaction between the genotype and the
Fig. 2. Effects of fosB KO on delta transfer latency between the first and second
trial in the elevated plus maze model of spatial learning. Results are expressed as
the mean (±S.E.M.) for fosB wild-type (+/+; n=8) and knock-out (KO; n=17) mice.
**p<0.01 versus +/+; unpaired Student’s t-test.
day was detected [F(12,336)=1.68, p=0.07]. fosB +/+ mice performed
significantly better than their −/− counterparts [F(2,43)=26.96,
p<0.0001] during the last day of training and attained above 90%
correct choices, as compared with 73.84±2.66% in the −/− group
(Fig. 2, right panel). Complementarily, prolongation of the inter-
val between the acquisition and the retention trials up to 20s,
also revealed the effect of genotype [F(1,56)=83.35 p<0.0001] and
time interval [F(1,56)=63.64 p<0.0001] but no effects of interaction
[F(1,56)=0.57, p=0.45]. fosB −/− mice performed at the chance level
scoring 47.7±3.6% of correct choices which is significantly lower
than fosB +/+ mouse (76.2±4.2%, p<0.001) results in the delayed
non-match to place task as revealed by Bonferroni post-hoc com-
could not result from the spontaneous perseverant behaviour, as
choices. Similarly, we have not found any significant “procedural”
perseverance, such as re-entering arms visited in the acquisition
phase (forced run).
3.4. Locomotor activity
Locomotor activity was measured in actometers during 2h of
testing in fosB +/+ (n=7) and −/− (n=7) mice. Two-way ANOVA
with repeated measures revealed a statistically significant effect
of time [F(8,96)=41.94, p<0.0001], however, no effects of fosB
knock-out [F(1,96)=0.02, p>0.05] or interaction between time and
genotype [F(8,96)=0.7, p>0.05] Level of locomotor activity, mea-
Fig. 3. Effects of fosB KO on the performance in the delayed non-match to place task in the T-maze during 13 days of training (left panel) and test session with 5- and 20-s
deletion between acquisition and retention phases (right panel). For each testing day percentage of correct choices was represented as the mean (±S.E.M.) for male wild-type
(+/+; n=16) and knock-out (−/−; n=14) mice. *** p<0.001 versus +/+ (5s),###p<0.001 versus +/+ (20s); two-way ANOVA with repeated measures; Bonferroni post-hock
W. Solecki et al. / Behavioural Brain Research 190 (2008) 212–217
Fig. 4. Effects of fosB KO on locomotor activity (panel A, fosB +/+: n=7; fosB −/−: n=7), depressive-like (panel B, fosB +/+: n=4; fosB −/−: n=6) and anxiety-like (panel C,
fosB +/+: n=6; fosB −/−: n=6) behaviours in mice, measured in actometers, forced swimming and four-plate tests, respectively. Results are expressed as the mean (±S.E.M.).
in Fig. 4, panel A.
3.5. Depressive and anxiety-like behaviours in the forced
swimming and four-plate tests
Time of immobility measured during 4min of forced swim-
ming test was higher in fosB +/+ (210±5.3s; n=4) than in −/−
(185±9.07s; n=6) mice (Fig. 4, panel B), however, unpaired Stu-
(t=2.07, d.f.=8 p>0.05) between tested groups. Similarly, unpaired
Student’s t-test analysis of performance in the four-plate test
showed no effect of genotype in the tested mice (t=0.42, d.f.=10
p>0.05). Number of electrical shocks received by tested mice did
not differ between fosB +/+ (3.3±0.7; n=6) and −/− (3.66±0.5;
n=6) mice (Fig. 4, panel C).
The present study demonstrates that morphine-induced con-
ditioned place preference (CPP) is abolished in mice lacking fosB
gene. It has been previously shown that fosB −/− mice display
enhanced cocaine and decreased nicotine reward sensitivity mea-
sured in CPP [17,45]. Complementarily to our results, it has been
reported that mice that exhibited inducible overexpression of delta
FosB in the nucleus accumbens (NAc) and dorsal striatum showed
increased sensitivity to rewarding effects of morphine measured in
CPP paradigm . Additionally, similar result has been reported
for rewarding effects of cocaine in mice with inducible overexpres-
sion of delta FosB in these brain regions .
Taken together, we can suggest that fosB is implicated in drug
rewarding effects which can be measured in CPP paradigm, how-
ever, the mechanisms of such role of fosB is not well understood.
It is known that overexpression of delta FosB in NAc and dorsal
increased FosB expression in the dorsal caudate-putamen and the
core but not the shell of the NAc is linked to the enhanced tendency
to work for a food reward in dopamine transporter knock-down
mice . On the other hand, Olausson et al.  suggested that
overexpression of delta FosB within the NAc could enhance food-
motivated behaviour, thereby regulating instrumental learning.
The issue arises whether fosB is necessary for expression
of rewarding effects produced by a certain stimulation or for
association of these effects with environmental stimuli, whose
motivational impact on animal behaviour is measured in CPP or
Drug-reinforced conditioned place preference paradigm is con-
sidered to rely on drug-reinforced learning, a type of associative
learning  in which subjective effects of drugs serve as rein-
forcement. Therefore, in control studies we decided to evaluate
fosB role in other types of learning. We found that fosB knock-out
mice display impaired learning and memory processes, since fosB
knock-out mice perform significantly worse than wild-type mice
in the elevated plus maze model of spatial learning and delayed
non-match to place task in the T-maze test.
cific spatial location [20,36]. The shorter latency to enter the “safe”
space on the second exposure serves as a measure of intact cogni-
tive functioning . Cognitive deficits observed in this test were
not due to differences in anxiety or sensorimotor function, since
fosB knock-out mice during first exposure to the test did not differ
in transfer latency in comparison to fosB wild-type mice.
In the T-maze test, we used non-match to place task in order
to investigate the spatial memory and spatial working memory. In
made by the subject was reinforced with palatable food reward.
Performance of fosB −/− in the T-maze test, when time between
the forced run and trial run was set on 5s, was higher than chance
level of 50%, which might illustrate some residual working mem-
ory. However, when the time between runs was increased up to
40s, fosB −/− mice could not respond correctly in this task, since
their performance (48%) was not different that the chance level. It
hippocampus-dependent and involves spatial memory and spatial
working memory [38,39].
Poor performance of fosB −/− mice in EPMSL and DNMTP tasks
implies spatial memory deficits in these mice. It has been reported
that fosB −/− mice display intact spatial navigation in the Morris
water-maze set-up . In contrast, in our study fosB −/− mice dis-
played spatial memory impairment, suggesting that such effects
are task-dependent. It is known that the Morris water-maze test,
especially the acquisition of this task is a strong stressful event for
mice, even when aversive factors are minimized [4,12,28]. There-
fore, procedural stress, involved in Morris water-maze test, may
confound the interpretation of the learning and memory-related
with specific genotype, has been shown to lead to altered pheno-
type, as shown in the studies of Alcaro et al.  and Orsini et al.
Discrepancy between employed learning/memory tests results
might also indicate involvement of non-cognitive behavioural
differences in fosB −/− phenotype, potentially confounding the
state and be related to both activity and anxiety . Therefore, we
decide to perform control studies, in which involvement of non-
cognitive behaviours such as locomotor activity, depressive-like
behaviours, anxiety or perseverant behaviours were evaluated. We
found no significant differences in locomotor activity (as measured
in actometers). However, it has been previously shown that fosB
W. Solecki et al. / Behavioural Brain Research 190 (2008) 212–217
−/− mice display enhanced locomotor activation in novel situation
sured in actometers, nor in CPP (measured as the number of arm
entries) nor in EPMSL studies (measured as transfer latency). Such
discrepancy might be due to prior familiarization and habituation
of animals to test conditions (i.e. apparatus, room) employed in our
Similarly, we found no significant differences in depression-like
or anxiety-like behaviours suggesting that the observed learn-
phenomena. What is more, implication of the spontaneous or pro-
cedural perseverance, which could similarly lead to the observed
deficits in the T-maze test was ruled out by an intra-group analysis
The immediate early gene fosB is a part of the AP-1 transcrip-
linked to neuronal plasticity [9,22]. McClung and Nestler  in a
microarray analysis characterized gene expression patterns in the
with neuroplasticity and motivational processes. BDNF was one of
such genes, which are known to enhance responding to drug- and
food-associated cues [14,25]. Another interesting gene is cyclin-
dependent kinase 5 , which is induced by delta FosB , and
can influence both the cocaine-induced structural plasticity 
and motivation as measured by progressive ratio responding for
natural or drug reinforcers (from  J.R. Taylor unpublished obser-
vations). GluR2 gene is also regulated by delta FosB and is known
that its expression is necessary for mice to exhibit cingulate LTD
The present series of experiments provides evidence that fosB
−/− mice display abolished morphine-induced CPP and cognitive
dysfunction related to spatial memory. Moreover, such results are
not due to altered locomotor, depressive or anxiety-like behaviours
since we did not find any differences in these behaviours between
fosB +/+ and −/− mice. These data provide evidence that fosB gene
may play an important role in the motivational aspects of rein-
forcers as well as in learning and memory processes.
None of the authors reported any actual or potential conflict of
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