The effects of Cd2+, Mn2+ and Al3+ on rat brain synaptosomal sodium-potassium-activated and magnesium-activated adenosine triphosphatase (Na-K-ATPase and Mg-ATPase) activity and choline uptake were studied. All three types of metal ions inhibited Na-K-ATPase activity more markedly than Mg-ATPase activity. The rank order of inhibition of Na-K-ATPase was: Cd2+ (ic50 = 5.4 μM) > Mn2+ (ic50 = 955 μm) > Al3+ (ic50 = 8.3 mM). The rank order of inhibition of Mg- was:Cd2+ (ic50 = 316 μM > Mn2+ (ic50 = 5.5 mM > Al3+ (ic50 = 21.9 mM). Al3+ was most potent in inhibiting synaptosomal choline uptake (ic50 = 24μM in the absence of Ca2+ and 123 μ.M in the presence of 1 mM Ca2+). Cd2+ (ic50 = 363 μM) was a more effective inhibitor of choline uptake than Mn2+(ic50 = 1.2−1.5 mM) . The presence of 1 mM Ca2+ did not alter choline uptake, nor did it antagonize the inhibitory actions of the three metals. Our observations that Cd2+ and Al3+ inhibited synaptosomal choline uptake, but did not show parallel inhibitory effects on Na-K-ATPase activity directly contradicts the ionic gradient hypothesis. These results are also discussed in relation to the in vivo neurotoxicity of cadmium, manganese and aluminium.