Glycogen synthase kinase 3beta in the nucleus accumbens core mediates cocaine-induced behavioral sensitization.
Glycogen synthase kinase 3beta (GSK-3beta) is a ubiquitous serine/threonine protein kinase involved in a number of signaling pathways. Previous studies have demonstrated a role for GSK-3beta in the synaptic plasticity underlying dopamine-associated behaviors and diseases. Drug sensitization is produced by repeated exposure to the drug and is thought to reflect neuroadaptations that contribute to addiction. However, the role of GSK-3beta in cocaine-induced behavior sensitization has not been examined. The present study investigated the effects of chronic cocaine exposure on GSK-3beta activity in the nucleus accumbens (NAc) and determined whether changes in GSK-3beta activity in the NAc are associated with cocaine-induced locomotor sensitization. We also explored whether blockade of GSK-3beta activity in the NAc inhibits the initiation and expression of cocaine-induced locomotor sensitization in rats using systemic or brain region-specific administration of the GSK-3beta inhibitors lithium chloride (LiCl) and SB216763. GSK-3beta activity in the NAc core, but not NAc shell, increased after chronic cocaine (10 mg/kg, i.p.) administration. The initiation and expression of cocaine-induced locomotor sensitization was attenuated by systemic administration of LiCl (100 mg/kg, i.p.) or direct infusion of SB216763 (1 ng/side) into the NAc core, but not NAc shell. Collectively, these results indicate that GSK-3beta activity in the NAc core, but not NAc shell, mediates the initiation and expression of cocaine-induced locomotor sensitization, suggesting that GSK-3beta may be a potential target for the treatment of cocaine addiction.
National Institute on Drug Dependence, Peking University, Beijing, China.
Chun-Mei
CM
Xu
Jun
J
Wang
Ping
P
Wu
Wei-Li
WL
Zhu
Qian-Qian
QQ
Li
Yan-Xue
YX
Xue
Hai-Fen
HF
Zhai
Jie
J
Shi
Lin
L
Lu
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D016739:Behavior, Addictive / Q000139:chemically induced* / Q000473:pathology*; D003042:Cocaine / Q000008:administration & dosage / Q000009:adverse effects*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D013997:Time Factors
D000276:Adjuvants, Immunologic; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C417521:SB 216763; D012694:Serine; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D003042:Cocaine