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

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.