title: 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.
abstract: 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 Meth-induced 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 (18)F-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 Meth-induced hyperactivity in Meth-sensitized Akt1(-/-) male mice. This study highlights a sex- and 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.
authors.affiliation: *To whom correspondence should be addressed; 1 Roosevelt Road, Sec. 4, Taipei 10617, Taiwan; tel: 886-2-3366-3112, fax: 886-2-3362-9909, e-mail: wslai@ntu.edu.tw.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Kao
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Min
authors.forename: Wen-Sung
authors.initials: WS
authors.lastname: Lai
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006948:Hyperkinesis / Q000139:chemically induced; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011605:Psychoses, Substance-Induced / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D020891:Raclopride / Q000008:administration & dosage / Q000494:pharmacology*; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology*; D012737:Sex Factors
chemical_list: D014150:Antipsychotic Agents; D001552:Benzazepines; D004967:Estrogens; C534628:SCH 23390; D020891:Raclopride; D008694:Methamphetamine; D004958:Estradiol; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: 17β-estradiol; Akt1 mice; behavioral sensitization; medium spiny neuron; meth-amphetamine use disorders; methamphetamine; microPET scan; schizophrenia; sex differences; striatum