The effects of chronic administration of lithium, short-term administration of lithium, chronic administration of DMI and a combination of short-term administration of lithium and chronic administration of DMI on second messenger responses were studied in the hippocampus of the rat. Lithium reduced the ability of carbachol to inhibit forskolin-stimulated activity of adenylate cyclase in hippocampal membranes but had no effect on carbachol-stimulated formation of inositol phosphate in hippocampal slices. Lithium, however, reduced the degree of stimulation of formation of inositol phosphate, induced by noradrenaline. Desimipramine alone did not affect carbachol- or noradrenaline-mediated reactions and a combination of short-term administration of lithium and chronic administration of DMI did not potentiate the action of lithium on adenylate cyclase. Both lithium and DMI abolished the inhibition by 5-HT of carbachol-stimulated formation of inositol phosphate a 5-HT1A receptor-mediated response. It is concluded that the chronic effects of administration of lithium may be related to actions at the G protein level and that different modes of coupling of receptors to G proteins may be responsible for the variety of effects observed.