Diverse Psychotomimetics Act Through a Common Signaling Pathway
Science November 21, 2003 Per Svenningsson, Eleni T. Tzavara, Robert Carruthers et al. 312 citations
Three drug classes—dopaminergic agonists (e.g., D-amphetamine), serotonergic agonists (e.g., LSD), and glutamatergic antagonists (e.g., PCP)—produce schizophrenia-like effects in animals. A common signaling pathway involving the protein DARPP-32 mediates these effects. DARPP-32 is phosphorylated or dephosphorylated at three sites, leading to synergistic inhibition of protein phosphatase-1 and regulation of downstream effectors GSK-3, CREB, and c-Fos. In mice lacking DARPP-32 or with point mutations at its phosphorylation sites, the drugs' effects on sensorimotor gating and repetitive movements were strongly reduced, indicating DARPP-32's essential role in these psychotomimetic actions.