The present invention provides methods and compositions for modulating the phosphorylation of DARPP-32 in a serotonergic receptor intracellular signaling pathway. The invention provides methods and compositions for modulating the activities of DARPP-32, casein kinase 1 (CK1), cyclin-dependent kinase 5 (Cdk5), AMPA receptors, protein phosphatase-1 (PP-1), protein phosphatase 2C (PP2C), protein phosphatase 2B (PP2B) and/or protein phosphatase 2A (PP2A) in cells or tissues. The invention provides methods of treating serotonergic intracellular signaling pathway disorders, e.g., depression. The invention provides methods of treating dopamine-related disorders. The invention provides methods of identifying agents that modulate the activities of serotonergic receptor intracellular signaling molecules, DARPP-32, casein kinase 1, cyclin-dependent kinase 5, AMPA receptors, protein phosphatase-1, protein phosphatase 2C, protein phosphatase 2B and/or protein phosphatase 2A, for use in such treatments. The invention also provides methods of modulating phosphorylation-dependent activation of AMPA receptors for use in such treatments.