Diverse psychotomimetics act through a common signaling pathway.
Three distinct classes of drugs: dopaminergic agonists (such as D-amphetamine), serotonergic agonists (such as LSD), and glutamatergic antagonists (such as PCP) all induce psychotomimetic states in experimental animals that closely resemble schizophrenia symptoms in humans. Here we implicate a common signaling pathway in mediating these effects. In this pathway, dopamine- and an adenosine 3',5'-monophosphate (cAMP)-regulated phospho-protein of 32 kilodaltons (DARPP-32) is phosphorylated or dephosphorylated at three sites, in a pattern predicted to cause a synergistic inhibition of protein phosphatase-1 and concomitant regulation of its downstream effector proteins glycogen synthesis kinase-3 (GSK-3), cAMP response element-binding protein (CREB), and c-Fos. In mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32, the effects of D-amphetamine, LSD, and PCP on two behavioral parameters-sensorimotor gating and repetitive movements-were strongly attenuated.
Pubmed ID: 14631045 RIS Download
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine | Animals | Brain | Central Nervous System Agents | Corpus Striatum | Cyclic AMP Response Element-Binding Protein | Dextroamphetamine | Dopamine | Dopamine and cAMP-Regulated Phosphoprotein 32 | Frontal Lobe | Genes, fos | Glycogen Synthase Kinase 3 | Glycogen Synthase Kinase 3 beta | Lysergic Acid Diethylamide | Male | Mice | Mice, Knockout | Motor Activity | Nerve Tissue Proteins | Phencyclidine | Phosphoprotein Phosphatases | Phosphoproteins | Phosphorylation | Protein Phosphatase 1 | RNA, Messenger | Receptors, Dopamine D1 | Reflex, Startle | Signal Transduction | Synaptic Transmission