Selective disruption of dopamine D2-receptors/beta-arrestin2 signaling by mood stabilizers

Mood stabilizers are a heterogeneous class of drugs having antidepressant and anti-manic effects in bipolar disorders, depression and schizophrenia. Despite wide clinical applications, the mechanisms underlying their shared actions and therapeutic specificity are unknown. Here, we examine the effects of the structurally unrelated mood stabilizers lamotrigine, lithium and valproate on G protein and beta-arrestin-dependent components of dopamine D2 receptor signaling and assess their contribution to the behavioral effects of these drugs. When administered chronically to mice lacking either D2 receptors or beta-arrestin 2, lamotrigine, lithium and valproate failed to affect Akt/GSK3 signaling as they do in normal littermates. This lack of effect on signaling resulted in a loss of responsiveness to mood stabilizers in tests assessing antimanic or antidepressant-like behavioral drug effects. This shows that mood stabilizers lamotrigine, lithium and valproate can exert behavioral effects in mice by disrupting the beta-arrestin 2-mediated regulation of Akt/GSK3 signaling by D2 dopamine receptors, thereby suggesting a shared mechanism for mood stabilizer selectivity.