title: Diverse psychotomimetics act through a common signaling pathway.
abstract: 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.
authors: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021, USA.
authors: Per
authors: P
authors: Svenningsson
authors: Eleni T
authors: ET
authors: Tzavara
authors: Robert
authors: R
authors: Carruthers
authors: Ilan
authors: I
authors: Rachleff
authors: Sigrid
authors: S
authors: Wattler
authors: Michael
authors: M
authors: Nehls
authors: David L
authors: DL
authors: McKinzie
authors: Allen A
authors: AA
authors: Fienberg
authors: George G
authors: GG
authors: Nomikos
authors: Paul
authors: P
authors: Greengard
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D016762:Genes, fos; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010622:Phencyclidine / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D015398:Signal Transduction; D009435:Synaptic Transmission
chemical_list: D002491:Central Nervous System Agents; D017362:Cyclic AMP Response Element-Binding Protein; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D008238:Lysergic Acid Diethylamide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D010622:Phencyclidine; D003913:Dextroamphetamine; D004298:Dopamine