Lithium has been used clinically in the treatment of manic depression. However, its pharmacologic mode of action remains unclear. Characteristics of Li ± interactions in red blood cells (RBCs) have been identified. We investigated Li + interactions on human neuroblastoma SH-SY5Y cells by developing a novel 7Li NMR method that provided a clear estimation of the intra-and extracellular amounts of LV in the presence of the shift reagent thulium-1,4,7,10tetrazacyclododecane-N , N', N", N"-tetramethylene phosphonate (HTmDOTP4). The first-order rate constants of Li + influx and efflux for perfused, agarose-embedded SH-SY5Y cells in the presence of 3 mM HTmDOTP4 were 0.055 ±0.006 (n = 4) and -0.025 ±0.006 min~1(n = 3), respectively. Significant increases in the rate constants of Li + influx and efflux in the presence of 0.05 mM veratridine indicated the presence of Nachannel-mediated Litransport in SH-SY5Y cells. 7Li NMR relaxation measurements showed that Li~is immobilized more in human neuroblastoma SH-SY5Y cells than in human RBCs. A 0, starting area of the intracellular resonance of Li * -loaded cells in Li + efflux measurements; A~, intracellular resonance area at time t; AA, atomic absorption; DIDS, 4,4 '-diisothiocyanatostilbene-2,2 '-disulfonic acid; DMEM, Dulbecco's modified Eagle's medium; HTmDOTP 4~, thulium-1,4,7,1 0-tetrazacyclododecane-N, N', N", N"-tetramethylenephosphonate; PCr, phosphocreatine; P,, inorganic phosphorus; ppm, parts per million; RBC, red blood cell; T,, spin-lattice relaxation value; T 2, spin-spin relaxation value; v0, initial rate of Li * influx.