Wortmannin, a potent phosphatidylinositol 3-kinase inhibitor, suppresses methamphetamine-induced stereotyped sniffing and biting, ameliorating the frequency of total stereotypy in mice

Abstract

Phosphatidylinositol 3-kinase (PI3K) (EC 2.7.1.137) is an enzyme essential for inflammation as well as carcinogenesis in mammals. It has been demonstrated that a close, positive relationship between expression of cellular inflammation and action of psychostimulants such as cocaine and methamphetamine (METH). This suggests that the inhibition of PI3K might regulate METH-induced positive symptoms such as hyperlocomotion and stereotyped behavior, but few reports have been made on animal research so far. In this presentation, we will demonstrate that pretreatment of mice with wortmannin (3 and 10 mg/kg), a potent and selective PI3K inhibitor, significantly inhibited METH-induced stereotypy in a dose-dependent fashion while METH-induced hyperlocomotion was not affected by pretreatment with wortmannin. It is of interest to present that a rearing behavior, which was not exhibited when mice with/without exposure to 10 mg/kg METH after 0 or 3 mg/kg wortmannin were exposed to a novel environment, was significantly augmented after exposure to 10 mg/kg METH after 10 mg/kg wortmannin, suggesting that a relatively high dose of wortmannin might shift stereotyped biting and sniffing to rearing.