Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates critical cellular processes such as proliferation, survival and migration as well as angiogenesis, allergic responses and immune responses. S1P exerts its function by activating S1P receptors (S1PRs). Fingolimod is an agonist of S1PRs and a new oral drug for multiple sclerosis. There are five S1PR subtypes: S1P ₁R, S1P ₂R, S1P ₃R, S1P ₄R and S1P ₅R. Fingolimod binds to all S1PR subtypes except S1P ₂R. It has been reported that S1PRs are expressed in many cell types including neurons, astrocytes, microglia and oligodendrocytes in the brain. There are few reports about a possible role of S1P and fingolimod in neurons. In this study, we investigated the effect of S1P and fingolimod on cAMP/PKA signaling in mouse striatal slices by monitoring the phosphorylation states of an intracellular phospho-protein, dopamine- and cAMP-regulated phosphoprotein of M _r 32 kDa (DARPP-32), in which Thr34 is phosphorylated by PKA. Treatment of slices with S1P (10 μM) or a selective S1P₁R agonist, SEW2871 (10 μM), increased DARPP-32 Thr34 phosphorylation at 1 min of incubation by 2-3-fold. Treatment of slices with fingolimod (100 nM) increased DARPP-32 Thr34 phosphorylation at 30 sec by 2-fold and decreased at 30 min by 0.6-fold. The increase in DARPP-32 phosphorylation induced by S1P was abolished by pre-treatment with a dopamine D₂ receptor agonist, quinpirole, or an adenosine A_2A receptor antagonist, ZM241385. Analysis using D₁-DARPP-32-Flag/D₂-DARPP-32-Myc transgenic mice revealed that activation of S1PRs by S1P increased DARPP-32 Thr34 phosphorylation in D₂-type/striatopallidal neurons, but not in D₁-type/striatonigral neurons. Thus, fingolimod likely activates cAMP/PKA signaling via activation of S1PRs selectively in D₂-type/striatopallidal neurons, and the effect is under control of D₂ and A_2A receptors.