GSK-3β activity and hyperdopamine-dependent behaviors

Dopamine plays important roles in normal brain function and many neuropsychiatric disorders. Classically, dopamine receptors are positively coupled to G protein-mediated signaling to regulate cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and Ca(2+) pathways. However, emerging evidence indicates that under hyperdopaminergic conditions, the protein kinase B (Akt)-glycogen synthase kinase 3β (GSK-3β) signaling cascade may mediate dopamine actions via D(2)-like receptors. This cAMP-independent signaling pathway involves the regulation of downstream synaptic targets, e.g., AMPA receptor, NMDA receptors, and thus synaptic plasticity. Here we provide an overview of how this novel signaling pathway relays dopamine receptor-mediated responses, particularly hyperdopamine-dependent behaviors. We discuss the relevance of the Akt/GSK-3β signaling cascade for the expression of dopamine-dependent behaviors and the drug actions associated with dopaminergic systems.