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Lithium, valproate and carbamazepine decrease brain cAMP. Adenylyl-cyclase (AC), which synthesizes cAMP has nine membrane-bound isoforms (AC1-AC9). In this study we used COS7 cells transfected with cDNA of each of the isoforms to study the effect of a therapeutic concentration of each of lithium, carbamazepine and valproate on ACs activity. AC5 was the most inhibitable isoform by lithium and carbamazepine either when stimulated by forskolin or by a D1 agonist. Ten mM Mg2+ reduced lithium-induced AC5 inhibition by 70% and in silico analysis suggested that carbamazepine preferentially affects AC1 and AC5 by interacting with two amino-acids at the catechol-estrogen binding site region. Valproate did not inhibit any AC isoform suggesting it decreases cAMP levels via a different mechanism. AC5 knockout mice behaved in the forced-swim-test similarly to antidepressant- or lithium-treated wildtypes implying that AC5 inhibition may be involved in the antidepressant effect of lithium and carbamazepine. Specific AC5 inhibitors may be mood-stabilizers or antidepressants.