Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade

TLDR

Dopamine regulates locomotion, emotion, cognition, and reward, and lithium salts are known to suppress dopamine‑associated behaviors in animal models, though the underlying mechanisms remain unclear. The study aimed to show that dopamine mediates its behavioral effects through a lithium‑sensitive Akt/GSK‑3 signaling cascade. In mouse striatum, heightened dopamine—induced by amphetamine or DAT loss—deactivates Akt and activates GSK‑3α/β, a change that is unaffected by cAMP but is reversed by blocking dopamine synthesis, D2 receptors, or by lithium administration. Pharmacological or genetic inhibition of GSK‑3 markedly reduces dopamine‑dependent locomotor activity, indicating that GSK‑3 is a key mediator of dopamine and lithium action and may be relevant to disorders such as ADHD and schizophrenia.

Abstract

Dopamine (DA) is a neurotransmitter involved in the control of locomotion, emotion, cognition, and reward. Administration of lithium salts is known to inhibit DA-associated behaviors in experimental animal models through unknown mechanisms. Here, we used a pharmacogenetic approach to show that DA can exert its behavioral effects by acting on a lithium-sensitive signaling cascade involving Akt/PKB and glycogen synthase kinase 3 (GSK-3). In the mouse striatum, increased DA neurotransmission arising either from administration of amphetamine or from the lack of the DA transporter results in inactivation of Akt and concomitant activation of GSK-3α and GSK-3β. These biochemical changes are not affected by activation of the cAMP pathway but are effectively reversed either by inhibition of DA synthesis, D2 receptor blockade, or administration of lithium salts. Furthermore, pharmacological or genetic inhibition of GSK-3 significantly reduces DA-dependent locomotor behaviors. These data support the involvement of GSK-3 as an important mediator of DA and lithium action in vivo and suggest that modulation of the Akt/GSK-3 pathway might be relevant to DA-related disorders, such as attention deficit hyperactivity disorder and schizophrenia.