The effects of GSK-3β blockade on ketamine self-administration and relapse to drug-seeking behavior in rats

Rationale: The role of glycogen synthase kinase-3 (GSK-3) has recently been implicated in the neuro-chemical mechanism underlying ketamine-induced neuronal toxicity and behavioral disturbance. Objectives: The primary goal of the present study was to determine the role of GSK-3 beta in ketamine self-administration (SA) and relapse to drug-seeking behavior after abstinence. Methods: In Experiment 1, the level of phosphorylated GSK-3 beta (p-GSK-3 beta) and total GSK-3 beta (t-GSK-3 beta) was determined in various brain areas following 14 days of ketamine SA. In Experiments 2 and 3, the effects of a GSK-3 beta inhibitor, SB216763 (2 and 4 mg/kg) and a GSK-3 inhibitor, lithium (LiCl, 100 mg/kg) on the responding maintained by 0.5 mg/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-3 beta inhibitor, or 100 mg/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-3 beta and t-GSK-3 beta (p-GSK-3 beta:t-GSK-3 beta) 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 4 mg/kg SB216763, whereas drug-induced relapse was inhibited by 2, 4 mg/kg SB216763 and LiCl. However, inactive responses were also suppressed by Lid 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. (C) 2014 Published by Elsevier Ireland Ltd.