Wortmannin, a potent phosphatidylinositol 3-kinase inhibitor, suppresses methamphetamine-induced stereotypy and hyperlocomotion in mice.

Abstract

Phosphatidylinositol 3-kinase (PI3K) (EC2.7.1.137) is an enzyme essential for a variety of biological processes, including inflammation and neuroplasticity. There is a close, positive relationship between these biological functions and the action of psychostimulant drugs such as cocaine and methamphetamine (METH). This suggests that the inhibition of PI3K might regulate METH-induced behavior such as hyperlocomotion and stereotyped behavior. To evaluate the effects of PI3K inhibition on METH-induced behavior, mice were treated with wortmannin, a potent PI3K inhibitor, followed by METH. Horizontal locomotion, vertical rearing, and stereotyped behaviors were measured. In addition, additional experiments were conducted to examine the effects of wortmannin on other aspects of behavior. Pretreatment of mice with wortmannin (3 and 10 mg/kg) significantly inhibited METH (10 mg/kg)-induced stereotyped behavior in a dose-dependent fashion. Stereotyped biting was most robustly reduced by wortmannin, ameliorating the frequency of total stereotypy. Wortmannin (10 but not 3 mg/kg) had a significant inhibitory effect on METH (3 mg/kg)-induced hyperlocomotion. Wortmannin had no effect on other aspects of behavior relevant to emotion or memory. In conclusion, non-glycogen synthase kinase-3β (GSK3β) mediated PI3K signaling pathways appear to contribute to the expression of acute METH effects on locomotion and stereotyped behavior in a manner that is different from PI3K-GSK3β mediated signaling.