Document Detail

Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade.
MedLine Citation:
PMID:  15044694     Owner:  NLM     Status:  MEDLINE    
Dopamine (DA) is a neurotransmitter involved in the control of locomotion, emotion, cognition, and reward. Administration of lithium salts is known to inhibit DA-associated behaviors in experimental animal models through unknown mechanisms. Here, we used a pharmacogenetic approach to show that DA can exert its behavioral effects by acting on a lithium-sensitive signaling cascade involving Akt/PKB and glycogen synthase kinase 3 (GSK-3). In the mouse striatum, increased DA neurotransmission arising either from administration of amphetamine or from the lack of the DA transporter results in inactivation of Akt and concomitant activation of GSK-3alpha and GSK-3beta. These biochemical changes are not affected by activation of the cAMP pathway but are effectively reversed either by inhibition of DA synthesis, D2 receptor blockade, or administration of lithium salts. Furthermore, pharmacological or genetic inhibition of GSK-3 significantly reduces DA-dependent locomotor behaviors. These data support the involvement of GSK-3 as an important mediator of DA and lithium action in vivo and suggest that modulation of the Akt/GSK-3 pathway might be relevant to DA-related disorders, such as attention deficit hyperactivity disorder and schizophrenia.
Jean-Martin Beaulieu; Tatyana D Sotnikova; Wei-Dong Yao; Lisa Kockeritz; James R Woodgett; Raul R Gainetdinov; Marc G Caron
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.     Date:  2004-03-24
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  101     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2004 Apr 
Date Detail:
Created Date:  2004-04-07     Completed Date:  2004-06-10     Revised Date:  2010-12-03    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5099-104     Citation Subset:  IM    
Howard Hughes Medical Institute, Department of Cell Biology and Center for Models of Human Disease, Institute of Genome Sciences and Policy, Duke University Medical Center, Durham, NC 27710, USA.
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MeSH Terms
Amphetamines / pharmacology
Behavior, Animal
Dopamine / physiology*
Glycogen Synthase Kinases / metabolism*
Lithium / pharmacology*
Mice, Inbred C57BL
Mice, Knockout
Protein-Serine-Threonine Kinases*
Proto-Oncogene Proteins / physiology*
Proto-Oncogene Proteins c-akt
Signal Transduction / physiology*
Grant Support
12043//Canadian Institutes of Health Research; DA-13511/DA/NIDA NIH HHS; MH-40159/MH/NIMH NIH HHS
Reg. No./Substance:
0/Amphetamines; 0/Proto-Oncogene Proteins; 7439-93-2/Lithium; EC 2.7.11.-/Glycogen Synthase Kinases; EC Kinases; EC Proteins c-akt

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