We have studied the effect of acute and chronic lithium treatment on the activity of striatal neurons recorded from corticostriatal slices. Under control conditions, tetanic stimulation of glutamatergic corticostriatal terminals caused long-term depression (LTD) of excitatory synaptic potentials. Acute lithium treatment did not affect the peak of the induction phase, but it reduced the following phases of LTD. LTD was completely blocked in slices obtained from rats chronically injected with LiCl. Lithium treatment failed to affect the intrinsic membrane properties of striatal neurons and the presynaptic inhibitory effects of carbachol and t-ACPD. We suggest that the lithium-induced blockade of LTD may contribute to the therapeutic action of lithium salts in mania and depression.