Aim:To explore the intracellular mechanisms underlying the survival/differentia-tion effect of the glial cell line-derived neurotrophic factor(GDNF)on dopamine(DA)cells.Methods:Midbrain slice culture and primary cell culture wereestablished,and the cultures were divided into 3 groups:control group,GDNFgroup,and the phosphatidylinositol 3-kinase/Akt(PI3-K/Akt)pathway-inhibitedgroup.Then the expression of tyrosine hydroxylase(TH)was detected byimmunostaining as well as Western blotting.Results:GDNF treatment inducedan increase in the number of TH-immunoreactive(ir)cells and the neurite numberof TH-ir cells,as well as in the level of TH expression in cultures(Number of TH-ir cells in the slice culture:control group,8.76±0.75;GDNF group,18.63±0.95.Number of TH-ir cells and neurite number of TH-ir cells in cell culture:controlgroup,3.65±0.88 and 2.49±0.42;GDNF group,6.01±0.43 and 4.89±0.46).Meanwhile,the stimulation of cultured cells with GDNF increased the phosphorylation of Akt,which is a downstream effector of PI3-K/Akt.The effects of GDNF were specifi-cally blocked by the inhibitor of the PI3-K/Akt pathway,wortmannin(Number ofTH-ir cells in slice culture:PI3-K/Akt pathway-inhibited group,6.98±0.58.Num-ber of TH-ir cells and neurite number of TH-ir cells in cell culture:PI3-K/Aktpathway-inhibited group,3.79±0.62 and 2.50±0.25,respectively).Conclusion:The PI3-K/Akt pathway mediates the survival/differentiation effect of GDNF onDA cells. Aim: To explore the intracellular mechanisms underlying the survival / differentia-tion effect of the glial cell line-derived neurotrophic factor (GDNF) on dopamine (DA) cells. Methods: Midbrain slice culture and primary cell culture wereestablished, and the cultures were divided into 3 groups: control group, GDNFgroup, and the phosphatidylinositol 3-kinase / Akt (PI3-K / Akt) pathway-inhibited group. The expression of tyrosine hydroxylase (TH) was detected by immunostaining as well as Western blotting. Results: GDNF treatment inducedan increase in the number of TH-immunoreactive (ir) cells and the neurite number of TH-ir cells, as well as in the level of TH expression in cultures (Number of TH-ir cells in the slice culture: control group, 8.76 ± 0.75; GDNF group, 18.63 ± 0.95. Number of TH-ir cells and neurite number of TH-ir cells in cell culture: controlgroup, 3.65 ± 0.88 and 2.49 ± 0.42; GDNF group, 6.01 ± 0.43 and 4.89 ± 0.46) , the stimulation of cultured cells with GDNF increased the phosphorylation of Akt, whic h is a downstream effector of PI3-K / Akt. these effects of GDNF were specifi-cally blocked by the inhibitor of the PI3-K / Akt pathway, wortmannin (Number of TH-ir cells in slice culture: PI3- K / Akt pathway -inhibited group, 6.98 ± 0.58.Num-ber of TH-ir cells and neurite number of TH-ir cells in cell culture: PI3-K / Aktpathway-inhibited group, 3.79 ± 0.62 and 2.50 ± 0.25, respectively) .Conclusion: The PI3-K / Akt pathway mediates the survival / differentiation effect of GDNF onDA cells.