title: The effects of GSK-3β blockade on ketamine self-administration and relapse to drug-seeking behavior in rats.
abstract: BACKGROUND
  The role of glycogen synthase kinase-3 (GSK-3) has recently been implicated in the neurochemical mechanism underlying ketamine-induced neuronal toxicity and behavioral disturbance.
  
  
  OBJECTIVE
  The primary goal of the present study was to determine the role of GSK-3β in ketamine self-administration (SA) and relapse to drug-seeking behavior after abstinence.
  
  
  METHODS
  In Experiment 1, the level of phosphorylated GSK-3β (p-GSK-3β) and total GSK-3β (t-GSK-3β) was determined in various brain areas following 14 days of ketamine SA. In Experiments 2 and 3, the effects of a GSK-3β inhibitor, SB216763 (2 and 4 mg/kg) and a GSK-3 inhibitor, lithium (LiCl, 100mg/kg) on the responding maintained by 0.5mg/kg/infusion ketamine SA were evaluated. In Experiments 4 and 5, rats underwent ketamine SA for 14 days followed by a 10-day abstinence period. The animals were treated with 2 or 4 mg/kg GSK-3β inhibitor, or 100mg/kg LiCl during the cue-induced relapse test. Seven days later, animals received the same drug treatment and underwent the drug-induced relapse test. Finally, the effect of saline and DMSO on locomotor activity was evaluated in Experiment 6.
  
  
  RESULTS
  Ketamine SA significantly decreased the ratio p-GSK-3β and t-GSK-3β (p-GSK-3β:t-GSK-3β) in the caudate putamen, nucleus accumbens, and ventral tegmental area. Both SB216763 and LiCl decreased responding on a progressive ratio schedule, but not on a fixed ratio schedule. Cue-induced relapse was suppressed only by 4mg/kg SB216763, whereas drug-induced relapse was inhibited by 2, 4 mg/kg SB216763 and LiCl. However, inactive responses were also suppressed by LiCl during progressive ratio and drug-induced relapse testing.
  
  
  CONCLUSIONS
  SB216763 was effective at decreasing ketamine SA under the PR schedule and reducing drug-seeking behavior after abstinence.
authors.affiliation: Ningbo University School of Medicine, 818 Fenghua Road, Ningbo 315211, Zhejiang, PR China.
authors.forename: Xianni
authors.initials: X
authors.lastname: Huang
authors.affiliation: Ningbo University School of Medicine, 818 Fenghua Road, Ningbo 315211, Zhejiang, PR China.
authors.forename: Kunyu
authors.initials: K
authors.lastname: Huang
authors.affiliation: Ningbo University School of Medicine, 818 Fenghua Road, Ningbo 315211, Zhejiang, PR China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Center for the Neurobiology of Addiction Treatment, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA; Ferring Pharmaceuticals Inc., 100 Interpace Pkwy, Parsippany, NJ 07054 USA.
authors.forename: Thomas J R
authors.initials: TJ
authors.lastname: Beveridge
authors.affiliation: Ningbo University School of Medicine, 818 Fenghua Road, Ningbo 315211, Zhejiang, PR China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Yang
authors.affiliation: Ningbo University School of Medicine, 818 Fenghua Road, Ningbo 315211, Zhejiang, PR China.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Li
authors.affiliation: Ningbo University School of Medicine, 818 Fenghua Road, Ningbo 315211, Zhejiang, PR China.
authors.forename: Pengping
authors.initials: P
authors.lastname: Li
authors.affiliation: Ningbo University School of Medicine, 818 Fenghua Road, Ningbo 315211, Zhejiang, PR China; Drug Addiction Research and Treatment Center of Ningbo, 42 Xibei St., Ningbo 315010, Zhejiang, PR China. Electronic address: whzhou@vip.163.com.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Ningbo University School of Medicine, 818 Fenghua Road, Ningbo 315211, Zhejiang, PR China. Electronic address: liuyu@nbu.edu.cn.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000494:pharmacology*; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D012008:Recurrence; D012055:Reinforcement Schedule; D012646:Self Administration; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
chemical_list: D007211:Indoles; D008301:Maleimides; C417521:SB 216763; D007649:Ketamine; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride
keywords: GSK-3β; Ketamine; Motivation; Relapse; Self-administration