The effect of lithium on noradrenaline-induced cyclic AMP accumulation in rat brain: Inhibition after chronic treatment and absence of supersensitivity

Lithium (Li) has been reported to inhibit numerous adenylate cyclases, but often these reports used clinically toxic concentrations of Li and their relevance to a theory of Li action was questionable. The present report demonstrated Li inhibition beginning at 2mM of the norepinephrine (NE)-induced cyclic AMP accumulation in a resuspended P₂ pellet containing intact synaptosomes and in slices from rat cortex. The inhibition is demonstrable with isoproterenol as well and in the presence of a phosphodiesterase inhibitor. In cortical slices removed from rats treated for 21 days with therapeutically equivalent Li serum levels, NE-induced cyclic AMP accumulation is inhibited by over 70%. After cessation of 21 or 42 days of Li treatment, an enhancement of cyclic AMP accumulation to NE is not demonstrable. Rubidium and cesium do not inhibit NE-induced cyclic AMP accumulation. These ions cause an increase in basal cyclic AMP accumulation in the absence of NE, as does Li to a lesser degree. The effect of Li to inhibit NE-induced cyclic AMP accumulation is therefore specific to the Li ion, occurs at therapeutically equivalent concentrations, continues after chronic treatment and does not cause a compensatory supersensitivity in the manner of the NE-receptor blocking drugs.