Background
The addictive properties of nicotine are mediated via dopaminergic pathways and their
post-synaptic neurons in the striatum. Because post-synaptic neurons within the striatum
contain high levels of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32),
we hypothesized that DARPP-32 may functionally contribute to the behavioral effects
of nicotine.
Methods
We examined the behavioral effects of nicotine and the phosphorylation state of DARPP-32
in wild-type (WT) and DARPP-32 knockout (KO) mice. In one experiment, we assessed
voluntary nicotine intake (0-50 μg/ml) of WT and KO mice in a two-bottle choice paradigm.
In a separate experiment, the motor-depressant effects of acute and repeated nicotine
injections (0–.8 mg/kg, subcutaneously [SC]) were assessed. The phosphorylation of
DARPP-32 at threonine34 and threonine75 were examined using Western blotting.
Results
A heightened responsiveness to nicotine was seen in KO mice when compared with WT
mice in oral intake and motor depression. The enhanced responsiveness in KO mice was
not due to alterations in taste sensations, fluid intake, or blood nicotine or cotinine
levels. Systemic injections of nicotine resulted in increased striatal DARPP-32 phosphorylation
at threonine34 and threonine75.
Conclusions
DARPP-32 opposes the behavioral effects of nicotine possibly via concurrent phosphorylation
at the two threonine sites.
Key Words
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Article info
Publication history
Published online: August 05, 2005
Accepted:
May 12,
2005
Received in revised form:
May 9,
2005
Received:
February 23,
2005
Identification
Copyright
© 2005 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
