Inhibition of specific adenylyl cyclase isoforms by lithium and carbamazepine, but not valproate, may be related to their antidepressant effect.
OBJECTIVE
Lithium, valproate, and carbamazepine decrease stimulated brain cyclic-AMP (cAMP) levels. Adenylyl cyclase (AC), of which there are nine membrane-bound isoforms (AC1-AC9), catalyzes the formation of cAMP. We have recently demonstrated preferential inhibition of AC5 by lithium. We now sought to determine whether carbamazepine and valproate also preferentially inhibit specific AC isoforms or decrease cAMP levels via different mechanisms.


METHODS
COS7 cells were transfected with one of AC1-AC9, with or without D1-dopamine receptors. Carbamazepine's and valproate's effect on forskolin- or D1 agonist-stimulated ACs was studied. The effect of Mg(2+) on lithium's inhibition was studied in membrane-enriched fraction from COS7 cells co-expressing AC5 and D1 receptors. AC5 knockout mice were tested for a behavioral phenotype similar to that of lithium treatment.


RESULTS
Carbamazepine preferentially inhibited forskolin-stimulated AC5 and AC1 and all D1 agonist-stimulated ACs, with AC5 and AC7 being the most sensitive. When compared to 1 or 3 mM Mg(2+), 10 mM Mg(2+) reduced lithium-induced AC5 inhibition by 70%. In silico modeling suggests that among AC isoforms carbamazepine preferentially affects AC1 and AC5 by interacting with the catechol-estrogen site. Valproate did not affect any forskolin- or D1 receptor-stimulated AC. AC5 knockout mice responded similarly to antidepressant- or lithium-treated wild-types in the forced-swim test but not in the amphetamine-induced hyperactivity mania model.


CONCLUSIONS
Lithium and carbamazepine preferentially inhibit AC5, albeit via different mechanisms. Lithium competes with Mg(2+), which is essential for AC activity; carbamazepine competes for AC's catechol-estrogen site. Antidepressant-like behavior of AC5 knockout mice in the forced-swim test supports the notion that AC5 inhibition is involved in the antidepressant effect of lithium and carbamazepine. The effect of lithium and carbamazepine to lower cAMP formation in AC5-rich dopaminergic brain regions suggests that D1-dopamine receptors in these regions are involved in the antidepressant effect of mood stabilizers.
Mann
Liad
L
Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Heldman
Eliahu
E
Bersudsky
Yuly
Y
Vatner
Stephen F
SF
Ishikawa
Yoshihiro
Y
Almog
Orna
O
Belmaker
Robert H
RH
Agam
Galila
G
D000262:Adenylyl Cyclases / Q000145:classification* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D019556:COS Cells; D002220:Carbamazepine / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects*; D007527:Isoenzymes / Q000172:deficiency; D008094:Lithium / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D045442:Rotarod Performance Test / Q000379:methods; D013550:Swimming / Q000523:psychology; D014162:Transfection; D014635:Valproic Acid / Q000494:pharmacology
D018692:Antimanic Agents; D001552:Benzazepines; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D007527:Isoenzymes; D005576:Colforsin; D002220:Carbamazepine; D014635:Valproic Acid; C071262:SK&F 82958; D008094:Lithium; D000661:Amphetamine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V