Huang Xianni, Huang Kunyu, Zheng Wenhui, Beveridge Thomas J R, Yang Shujun, Li Xingxing, Li Pengping, Zhou Wenhua, Liu Yu
Ningbo University School of Medicine, 818 Fenghua Road, Ningbo 315211, Zhejiang, PR China.
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.
Drug Alcohol Depend. 2015 Feb 1;147:257-65. doi: 10.1016/j.drugalcdep.2014.10.028. Epub 2014 Nov 15.
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.
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.
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.
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.
SB216763 was effective at decreasing ketamine SA under the PR schedule and reducing drug-seeking behavior after abstinence.
糖原合酶激酶-3（GSK-3）的作用最近被认为与氯胺酮诱导的神经元毒性和行为障碍的神经化学机制有关。
本研究的主要目的是确定GSK-3β在氯胺酮自我给药（SA）及戒断后复吸觅药行为中的作用。
在实验1中，测定氯胺酮自我给药14天后，各个脑区中磷酸化GSK-3β（p-GSK-3β）和总GSK-3β（t-GSK-3β）的水平。在实验2和3中，评估GSK-3β抑制剂SB216763（2和4mg/kg）和GSK-3抑制剂氯化锂（LiCl，100mg/kg）对0.5mg/kg/次注射氯胺酮自我给药维持的反应的影响。在实验4和5中，大鼠进行14天的氯胺酮自我给药，随后有10天的戒断期。在提示诱导的复吸试验期间，给动物注射2或4mg/kg的GSK-3β抑制剂，或100mg/kg的LiCl。7天后，动物接受相同的药物治疗并进行药物诱导的复吸试验。最后，在实验6中评估生理盐水和二甲基亚砜对运动活性的影响。
氯胺酮自我给药显著降低了尾壳核、伏隔核和腹侧被盖区中p-GSK-3β与t-GSK-3β的比值（p-GSK-3β:t-GSK-3β）。SB216763和LiCl均降低了累进比率程序下的反应，但在固定比率程序下未降低。仅4mg/kg的SB216763抑制提示诱导的复吸，而2、4mg/kg的SB216763和LiCl抑制药物诱导的复吸。然而，在累进比率和药物诱导的复吸试验期间，LiCl也抑制了无效反应。
SB216763在累进比率程序下有效降低氯胺酮自我给药，并减少戒断后的觅药行为。
