Inhibition of GSK3 attenuates amphetamine-induced hyperactivity and sensitization in the mouse

► Amphetamine-induced hyperactivity was attenuated by valproate or SB 216763. ► Valproic acid increased GSK3 phosphorylation in amphetamine-treated mice. ► Valproic acid and SB 216763 attenuated the development of amphetamine-induced sensitization. ► We conclude that GSK3 activation is important for amphetamine-induced hyperactivity and the development of sensitization to stereotypy. 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 (50–300mg/kg, i.p.) or SB 216763 (2.5–5mg/kg, i.p.) prior to amphetamine (2mg/kg, i.p.) significantly reduced amphetamine-induced ambulation and stereotypy. To assess the development of sensitization to the stereotypic effects of amphetamine, mice were pretreated daily with valproic acid (300mg/kg) or SB 216763 (5mg/kg) prior to amphetamine (2mg/kg) for 5 days. Upon amphetamine challenge (1mg/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 (300mg/kg) or vehicle was injected prior to amphetamine (2mg/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.