CELLULAR, MOLECULAR AND DEVELOPMENTAL NEUROSCIENCELithium normalizes amphetamine-induced changes in striatal FoxO1 phosphorylation and behaviors in ratsZheng, Wenhuaa,b; Zeng, Zhiwena,c; Bhardwaj, Sanjeev K.c; Jamali, Sarac; Srivastava, Lalit K.cAuthor Information aDepartment of Neuropharmacology, School of Pharmaceutical Sciences bState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China cDepartment of Psychiatry, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada Correspondence to Lalit K. Srivastava, PhD, Department of Psychiatry, Douglas Mental Health University Institute, 6875 LaSalle Blvd, Montreal, Quebec, Canada H4H 1R3 Tel: +1 514 761 6131; fax: +1 514 762 3034; e-mail: [email protected] Received March 5, 2013 Accepted April 15, 2013 NeuroReport: July 10, 2013 - Volume 24 - Issue 10 - p 560-565 doi: 10.1097/WNR.0b013e3283623725 Buy Metrics Abstract Administration of the psychostimulant drug amphetamine (AMPH) to animals causes hyperactivity and deficit in prepulse inhibition (PPI) of startle, behaviors that are often observed in neuropsychiatric disorders such as schizophrenia and bipolar disorder. Enhanced central dopamine (DA) transmission is believed to mediate AMPH-induced behavioral alterations. Lithium, a drug used primarily in the treatment of bipolar disorder, is reported to interact with the DA system and antagonize some DA-related behaviors. Here, we provide evidence that AMPH and lithium reciprocally regulate the activity of the transcription factor forkhead box, class O1 (FoxO1), a downstream target of Akt. Administration of d-AMPH (3 mg/kg, intraperitoneally) to Sprague–Dawley rats resulted in a concomitant decrease in levels of phosphorylated (p) Akt as well as p-FoxO1 in the striatum, whereas lithium chloride (LiCl,100 mg/kg, intraperitoneally) exerted the opposite effect, that is, it increased levels of p-Akt and p-FoxO1. Pretreatment of animals with lithium prevented an AMPH-induced decrease in striatal p-Akt and p-FoxO1 levels. Pretreatment of animals with lithium also attenuated AMPH-induced locomotor activity and decreased prepulse inhibition. These in-vivo data suggest that the Akt–FoxO1 pathway may be a common target for the action of dopaminergic and antidopaminergic drugs, and its modulation may be relevant to the treatment of neuropsychiatric disorders. © 2013 Lippincott Williams & Wilkins, Inc.