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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

Authors

  • Svenningsson P
  • Tzavara ET
  • Carruthers R
  • Rachleff I
  • Wattler S
  • Nehls M
  • McKinzie DL
  • Fienberg AA
  • Nomikos GG
  • Greengard P

Journal

Science (New York, N.Y.)

Publication Data

November 21, 2003

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA10044
  • Agency: NIMH NIH HHS, Id: MH40899

Mesh Terms

  • 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
  • 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