Cocaine-induced elevations in FosB/?FosB correlate with increased drug reward and decreased novelty reward.

1
Cocaine-induced elevations in FosB/?FosB
correlate with increased drug reward and
decreased novelty reward. S.D. Mague1, M.
Wimmer1, G.C. Harris1 and G. Aston-Jones2 1.Neuros
cience Graduate Program, University of
Pennsylvania, Philadelphia, PA 2. Department of
Neurosciences, Medical University of South
Carolina, Charleston, SC
INTRODUCTION
Only in the NAc-shell do FosB/?FosB counts
correlate with increased cocaine and decreased
novelty preference following both 2 and 5 weeks
of drug abstinence
Cocaine withdrawn animals show an altered hedonic
response to natural and drug rewards.
Chronic cocaine treatment elevates FosB/?FosB
staining in the NAc-shell, NAc-core, and BLA.
b.
a.
Rats treated chronically with morphine or cocaine
show an increased preference for drug rewards,
but a decreased preference for natural rewards1.
?FosB accumulates in reward-related brain
regions following chonic exposure to drugs of
abuse2. It has been suggested that the stability
of ?FosB could explain the long-lasting effects
of chronic drug exposure3. HYPOTHESIS If ?FosB
accumulation is responsible for alterations in
hedonic processing, then elevations in FosB/?FosB
in reward-related brain regions following chronic
cocaine exposure should correlate with increases
in acute cocaine preference and decreases in
novel-object preference.
Figure 2. Example of coronal brain sections
stained for FosB/?FosB in cocaine withdrawn (a)
and saline animals (b). Rats were perfused 2 h
after preference test in cocaine CPP. Ac nucleus
accumbens, BLA basolateral amygdala, CE central
amygdala, LA lateral amygdala.
A
B
Figure 4. Correlation R values for FosB/?FosB
counts (NAc-shell, NAc-core, and BLA) and CPP
scores in animals undergoing novel-object (red)
or cocaine (blue) place-conditioning studies. n
10-14.
Only in the NAc-shell is FosB/?FosB elevated
following both 2 and 5 weeks of cocaine
abstinence.
a.
b.
Experimental Design
CONCLUSIONS

1. Cocaine exposure followed by 2 to 5 weeks of
   abstinence results in altered hedonic processing
   in which cocaine cues become more highly
   rewarding, and novel-object cues become less
   rewarding.
2. FosB/?FosB is elevated in several reward-related
   brain regions following 2-3 weeks of cocaine
   abstinence. However, only in the NAc-shell is
   FosB/?FosB accumulation still elevated after 5
   weeks of withdrawal.
3. Increased cocaine preference and decreased
   novel-object preference after 5 weeks of drug
   abstinence correlate with elevated FosB/?FosB
   counts only in the NAc-shell, suggesting that
   this brain region may be responsible for the
   alteration in hedonic processing.

10-day Coc
2-5 week abstinence
Coc/Novelty CPP
CPP Box
Novel Objects
Figure 1. Preference scores for the novel
object-paired (a) or cocaine-paired (b)
environment expressed as the mean time (in
seconds) spent in the paired side minus the mean
time spent on the non-paired side on the test
day. plt.01 n 10-14.
Cocaine Conditioning Rats received an injection
of cocaine (10 mg/kg i.p.) and were placed in one
chamber for 30 min 4 hours later they were
injected with saline and placed in the other
chamber. The order of pairings alternated daily.
Animals were conditioned for 3 consecutive days.
Novelty Conditioning Rats were exposed to a
novel object in one chamber for 10 min 1 hour
later they were exposed to the other chamber
without an object. The order of pairings
alternated daily for 8 days a different object
was used each day. Test Day 24 hr following
the final conditioning day, rats were tested for
cocaine or novel-object preference by allowing
free access to both chambers for a 15 min
session. Animals were perfused 2 hr after this
test session and tissue was prepared for
FosB/?FosB staining. For all experiments, male
Sprague-Dawley rats 300-350g were used.
Immunoreactivity Coronal brain sections from
animals in the above experiment were reacted with
antibodies targeting the FosB/?FosB protein
(1500, Santa Cruz Biotechnology, Inc), incubated
with the secondary antibody (biotinylated goat
anti-rabbit 1500, Jackson Immunoresearch
Laboratories, West Grove, PA) and an avidin
biotin complex, and visualized with DAB and
nickel ammonium sulfate.
References

1. Harris, G.C. Aston-Jones, G. (2003)
   Neuropsychopharm 28, 865-871.
2. Chen, J.S., Zhang, Y.J., Kelz, M.B., Steffen, C.,
   Ang, E.S., Zeng, L. Nestler, E.J. (2000) J.
   Neurosci. 20, 8965-8971.
3. Nestler, E.J., Barrot, M. Self, D.W. (2001)
   Proc. Natl. Acad. Sci. USA 98 11042-11046.

Figure 3. FosB/?FosB counts in NAc-shell,
NAc-core, and BLA either 2 or 5 weeks following
chronic administration of cocaine or saline in
animals undergoing novel-object (a) or cocaine
(b) place conditioning studies. plt.01 n
10-14.
Research supported by PHS grants DA06214 and
DA017289.