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

Abstract

RationaleThe role of glycogen synthase kinase-3 (GSK-3) has recently been implicated in the neurochemical mechanism underlying ketamine-induced neuronal toxicity and behavioral disturbance. ObjectivesThe 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. MethodsIn 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 4mg/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 4mg/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. ResultsKetamine 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, 4mg/kg SB216763 and LiCl. However, inactive responses were also suppressed by LiCl during progressive ratio and drug-induced relapse testing. ConclusionsSB216763 was effective at decreasing ketamine SA under the PR schedule and reducing drug-seeking behavior after abstinence.