Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
Behav Brain Res. 2012 May 16;231(1):217-25. doi: 10.1016/j.bbr.2012.03.027.
Glycogen synthase kinase 3 (GSK3) is implicated in mediating dopamine-dependent behaviors. Previous studies have demonstrated the ability of amphetamine, which increases extracellular dopamine levels and influences behavior, to regulate the activity of GSK3. This study used valproic acid and the selective GSK3 inhibitor, SB 216763, to examine the role of GSK3 in amphetamine-induced hyperactivity and the development of sensitized stereotypic behavior. Pretreatment with valproic acid (50-300 mg/kg, i.p.) or SB 216763 (2.5-5 mg/kg, i.p.) prior to amphetamine (2 mg/kg, i.p.) significantly reduced amphetamineinduced ambulation and stereotypy. To assess the development of sensitization to the stereotypic effects of amphetamine, mice were pretreated daily with valproic acid (300 mg/kg) or SB 216763 (5 mg/kg) prior to amphetamine (2 mg/kg) for 5 days. Upon amphetamine challenge (1 mg/kg) 7 days later, mice pretreated with valproate or SB 216763 showed a significant attenuation of amphetamine-induced sensitization of stereotypy. To determine whether regulation of GSK3 activity was associated with attenuation of acute amphetamine-induced hyperactivity by valproic acid, valproate (300 mg/kg) or vehicle was injected prior to amphetamine (2 mg/kg) or saline and brain tissue obtained. Analysis of the levels of phospho-GSK3α and β by immunoblot indicated that valproate increased phosphorylation of ser²¹-GSK3α in the frontal cortex, as well as ser⁹-GSK3β in the frontal cortex and caudate putamen of amphetamine-injected mice. These data support a role for GSK3 in acute amphetamine-induced hyperactivity and the development of sensitization to amphetamine-induced stereotypy.
糖原合酶激酶 3（GSK3）参与介导多巴胺依赖性行为。先前的研究已经证明，增加细胞外多巴胺水平并影响行为的安非他命能够调节 GSK3 的活性。本研究使用丙戊酸钠和选择性 GSK3 抑制剂 SB 216763 来研究 GSK3 在安非他命诱导的过度活跃和敏化刻板行为发展中的作用。在安非他命（2 mg/kg，ip）之前预先给予丙戊酸钠（50-300 mg/kg，ip）或 SB 216763（2.5-5 mg/kg，ip）预处理显著减少了安非他命诱导的走动和刻板行为。为了评估对安非他命刻板效应的敏化作用的发展，小鼠在安非他命（2 mg/kg）之前每天预先用丙戊酸钠（300 mg/kg）或 SB 216763（5 mg/kg）预处理，持续 5 天。7 天后，在用安非他命（1 mg/kg）进行安非他命挑战时，用丙戊酸钠或 SB 216763 预处理的小鼠表现出对安非他命诱导的刻板行为敏化的显著减弱。为了确定 GSK3 活性的调节是否与丙戊酸钠对急性安非他命诱导的过度活跃的抑制作用有关，在安非他命（2 mg/kg）或生理盐水之前注射丙戊酸钠（300 mg/kg）或载体，并获得脑组织。通过免疫印迹分析磷酸化 GSK3α 和 β 的水平表明，丙戊酸钠增加了前额皮质中丝氨酸 21-GSK3α 的磷酸化，以及在安非他命注射小鼠的前额皮质和尾状核苍白球中的丝氨酸 9-GSK3β 的磷酸化。这些数据支持 GSK3 在急性安非他命诱导的过度活跃和对安非他命诱导的刻板行为的敏化发展中的作用。
