THE EFFECT OF LITHIUM ON NORADRENALINE-INDUCED CYCLIC-AMP ACCUMULATION IN RAT-BRAIN - INHIBITION AFTER CHRONIC TREATMENT AND ABSENCE OF SUPER-SENSITIVITY

Abstract

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 2 mM of the norepinephrine (NE)-induced cyclic[c]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 [Rozo 1724]. In cortical slices removed from rats treated for 21 days with therapeutically equivalent Li serum levels, NE-induced cAMP accumulation is inhibited by over 70%. After cessation of 21 or 42 days of Li treatment, an enhancement of cAMP accumulation to NE is not demonstrable. Rubidium and cesium do not inhibit NE-induced cAMP accumulation. These ions cause an increase in basal cAMP accumulation in the absence of NE, as does Li to a lesser degree. The effect of Li to inhibit NE-induced cAMP accumulation is 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. [Li is an effective drug in the treatment of manic-depressive illness.].