DARPP-32 phosphorylation opposes the behavioral effects of nicotine.
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 microg/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.
Zhu
Hongwen
H
Laboratory of Molecular Psychobiology, Albert Einstein College of Medicine, Bronx, NY, USA.
Lee
MoonSook
M
Guan
Fangxia
F
Agatsuma
Soh
S
Scott
Daniel
D
Fabrizio
Kevin
K
Fienberg
Allen A
AA
Hiroi
Noboru
N
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western; D003367:Cotinine / Q000097:blood; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000502:physiology*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000097:blood / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010766:Phosphorylation
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018722:Nicotinic Agonists; D009538:Nicotine; D003367:Cotinine