PT - JOURNAL ARTICLE AU - Yan Xia AU - Cheng Z. Wang AU - Jie Liu AU - Noelle C. Anastasio AU - Kenneth M. Johnson TI - Lithium Protection of Phencyclidine-Induced Neurotoxicity in Developing Brain: The Role of Phosphatidylinositol-3 Kinase/Akt and Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signaling Pathways AID - 10.1124/jpet.107.133272 DP - 2008 Sep 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 838--848 VI - 326 IP - 3 4099 - http://jpet.aspetjournals.org/content/326/3/838.short 4100 - http://jpet.aspetjournals.org/content/326/3/838.full SO - J Pharmacol Exp Ther2008 Sep 01; 326 AB - Phencyclidine (PCP) and other N-methyl-d-aspartate (NMDA) receptor antagonists have been shown to be neurotoxic to developing brains and to result in schizophrenia-like behaviors later in development. Prevention of both effects by antischizophrenic drugs suggests the validity of PCP neurodevelopmental toxicity as a heuristic model of schizophrenia. Lithium is used for the treatment of bipolar and schizoaffective disorders and has recently been shown to have neuroprotective properties. The present study used organotypic corticostriatal slices taken from postnatal day 2 rat pups to investigate the protective effect of lithium and the role of the phosphatidylinositol-3 kinase (PI-3K)/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways in PCP-induced cell death. Lithium pretreatment dose-dependently reduced PCP-induced caspase-3 activation and DNA fragmentation in layers II to IV of the cortex. PCP elicited time-dependent inhibition of the MEK/ERK and PI-3K/Akt pathways, as indicated by dephosphorylation of ERK1/2 and Akt. The proapoptotic factor glycogen synthase kinase (GSK)-3β was also dephosphorylated at serine 9 and thus activated. Lithium prevented PCP-induced inhibition of the two pathways and activation of GSK-3β. Furthermore, blocking either PI-3K/Akt or MEK/ERK pathway abolished the protective effect of lithium, whereas inhibiting GSK-3β activity mimicked the protective effect of lithium. However, no cross-talk between the two pathways was found. Finally, specific GSK-3β inhibition did not prevent PCP-induced dephosphorylation of Akt and ERK. These data strongly suggest that the protective effect of lithium against PCP-induced neuroapoptosis is mediated through independent stimulation of the PI-3K/Akt and ERK pathways and suppression of GSK-3β activity. The American Society for Pharmacology and Experimental Therapeutics