The therapeutic action of lithium in affective disorders is still unclear. One effect of lithium is to deplete membrane inositol and consequently to exhaust the phosphoinositide (PI) pathway. Under chronic lithium treatment, rats showed persistent performance deficits in an active avoidance task and in a visually cued maze. The same treatment, however, resulted in only a transient deficit in the performance of rats in a spatial memory task. Lithium treatment caused a similarly transient deficit in the ability of acetylcholine to potentiate responses to N-methyl-D-aspartate (NMDA) in neurons of the hippocampal slice. The authors propose that the development of compensatory mechanisms may account for the lack of severe memory impairments during lithium treatment. It is suggested that the effects of lithium on the PI pathway are not sufficient to explain the behavioral consequences of chronic lithium treatment.