Pretreatment with LY2090314, a potent glycogen synthase kinase-3 inhibitor, suppresses methamphetamine-induced stereotyped behavior but not hyperlocomotion in mice.

Neuronal glycogen synthase kinase-3s (GSK-3α and the more abundant GSK-3β) are serine/threonine kinases that have been postulated to play roles in neuronal adaptations, including those that come from exposures to substances of abuse; however, there is only modest information about ways in which GSK-3 alters the effects of the widely abused psychostimulant, methamphetamine (METH). To evaluate the effects of GSK-3 inhibition on METH-induced symptoms, mice were treated with LY2090314, a potent and selective GSK-3 inhibitor, followed by METH. Horizontal locomotion, vertical rearing, and stereotyped behaviors were measured. Pretreatment with LY2090314 (2.5, 10, and 25 mg/kg) significantly inhibited stereotypic behavior induced by METH (10 mg/kg) in a dose-dependent fashion. Stereotyped biting was most robustly reduced by LY2090314. By contrast, LY2090314 had no significant effect on METH (3 mg/kg)-induced hyperlocomotion. GSK-3 signaling pathways appear to be differentially involved in acute METH effects on locomotion. GSK-3 appears essential for the expression of METH-induced stereotypy but not hyperlocomotion.