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

Abstract

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 amphetamine-induced 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 five days. Upon amphetamine challenge (1 mg/kg) seven 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.

The effect of sertindole on behavioural sensitisation to methamphetamine in mice

“…This phenomenon is termed behavioural sensitisation and was described for the first time by Robinson and Berridge (1993). Behavioural sensitisation occurs not only for psychostimulants -amphetamine (Enman and Unterwald 2012;Fukushiro et al 2012) or cocaine (Aracil-Fernandez et al 2012;Ramos et al 2012) but also for other psychotropic substances -e.g., morphine (Hofford et al 2012;Niu et al 2012), delta(9)-tetrahydrocannabinol (Cadoni et al 2008), ethanol (Bahi and Dreyer 2012) and nicotine (Lee et al 2012).…”

Differential effects of glycogen synthase kinase 3 (GSK3) inhibition by lithium or selective inhibitors in the central nervous system

“…Previous findings in a transgenic mouse model demonstrated that this action is mediated by GSK3 at least in part (Ahnaou and Drinkenburg 2011). Other studies based on pharmacological inhibition of GSK3 provided further support to this hypothesis (Miller et al 2009;Enman and Unterwald 2012;Kozikowski et al 2011;Xu et al 2011;Kalinichev and Dawson 2011). Thus, mice were tested in amphetamineinduced hyperlocomotor activity.…”

Regulation of GSK-3 Activity as A Shared Mechanism in Psychiatric Disorders

“…It has been well reported that changes in dopaminergic activity are highly related to ADHD and treatment with psychostimulants such as amphetamine or methylphenidate results in GSK-3 activation coupled with increased locomotion in experimental studies 76,77 . In addition, administration of GSK-3 inhibitors such as lithium reduces amphetamine-induced hyperactivity in mice 78 .…”