A Sex- and Region-Specific Role of Akt1 in the Modulation of Methamphetamine- Induced Hyperlocomotion and Striatal Neuronal Activity: Implications in Schizophrenia and Methamphetamine-Induced Psychosis Yi-Wen Chen1, Hui-Yun Kao2, Ming-Yuan Min2,3,4, and Wen-Sung Lai*,1,3,4

AKT1 (also known as protein kinase B, α), a serine/threonine kinase of AKT family, has been implicated in both schizophrenia and methamphetamine (Meth) use disorders. AKT1 or its protein also has epistatic effects on the regulation of dopamine-dependent behaviors or drug effects, especially in the striatum. The aim of this study is to investigate the sex-specific role of Akt1 in the regulation of Meth-induced behavioral sensitization and the alterations of striatal neurons using Akt1−/− mice and wild-type littermates as a model. A series of 4 Experiments were conducted. Meth-induced hyperlocomotion and Meth-related alterations of brain activity were measured. The neural properties of striatal medium spiny neurons (MSNs) were also characterized. Further, 17β-estradiol was applied to examine its protective effect in Meth-sensitized male mice. Our findings indicate that (1) Akt1−/− males were less sensitive to Methinduced hyperlocomotion during Meth challenge compared with wild-type controls and Akt1−/− females, (2) further sex differences were revealed by coinjection of Meth with raclopride but not SCH23390 in Meth-sensitized Akt1−/− males, (3) Meth-induced alterations of striatal activity were confirmed in Akt1−/− males using microPET scan with 18F-flurodeoxyglucose, (4) Akt1 deficiency had a significant impact on the electrophysiological and neuromorphological properties of striatal MSNs in male mice, and (5) subchronic injections of 17β-estradiol prevented the reduction of Methinduced hyperactivity in Meth-sensitized Akt1−/− male mice. This study highlights a sexand region-specific effect of Akt1 in the regulation of dopamine-dependent behaviors and implies the importance of AKT1 in the modulation of sex differences in Meth sensitivity and schizophrenia.