The Journal of Neuroscience, September 15, 2002, 22(18):7844-7849
BRIEF COMMUNICATION
The Role of Corticotropin-Releasing Factor in the Median Raphe
Nucleus in Relapse to Alcohol
A. D.
Lê1, 2, 3,
S.
Harding1,
W.
Juzytsch1,
P. J.
Fletcher1, 2, 3, 4, and
Y.
Shaham5
1 Department of Neuroscience, Center for
Addiction and Mental Health, Toronto, Ontario, Canada M5S 2S1,
Departments of 2 Pharmacology, 3 Psychiatry,
and 4 Psychology, University of Toronto, Toronto, Ontario,
Canada M5S 1A8, and 5 Behavioral Neuroscience Branch,
National Institute on Drug Abuse Intramural Research Program,
Baltimore, Maryland 21044
Using an animal model of drug relapse, we found that intermittent
footshock stress reinstates alcohol seeking, an effect attenuated by
the 5-HT reuptake blocker fluoxetine and by corticotropin-releasing factor (CRF) receptor antagonists. Here we studied the role of the 5-HT
cell body region of the median raphe nucleus (MRN) and CRF receptors in
this site in reinstatement of alcohol seeking. Rats were given alcohol
in a two-bottle choice procedure (water vs alcohol) for 25 d and
were then trained for 1 hr/d to press a lever for alcohol (12% w/v)
for 23-30 d. Subsequently, lever pressing for alcohol was extinguished
by terminating drug delivery for 5-9 d. Tests for reinstatement of
alcohol seeking were then performed under extinction conditions.
Intra-MRN infusions of 8-OH-DPAT
[8-hydroxy-2-(di-n-propylamino)tetralin] (a
5-HT1A agonist that decreases 5-HT cell firing and release)
reinstated alcohol seeking. Reinstatement of alcohol seeking also was
observed after intra-MRN infusions of low doses of CRF (3-10 ng),
which mimicked the effect of ventricular infusions of higher doses of
the peptide (300-1000 ng). Finally, intra-MRN infusions of the CRF
receptor antagonist d-Phe CRF (50 ng) blocked the effect
of intermittent footshock (10 min) on reinstatement. These data suggest
that an interaction between CRF and 5-HT neurons within the MRN is
involved in footshock stress-induced reinstatement of alcohol seeking.
Key words:
alcohol; corticotropin-releasing factor; reinstatement; relapse; serotonin; stress
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