Diverse Psychotomimetics Act through a Common Signaling Pathway

• Published in: Science (American Association for the Advancement of Science) Vol. 302; no. 5649; pp. 1412 - 1415
• Main Authors: Svenningsson, Per, Tzavara, Eleni T., Carruthers, Robert, Rachleff, Ilan, Wattler, Sigrid, Nehls, Michael, McKinzie, David L., Fienberg, Allen A., Nomikos, George G., Greengard, Paul
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 21-11-2003; The American Association for the Advancement of Science
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology; Amines; Amphetamines; Animals; Behavioral neuroscience; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Central Nervous System Agents - pharmacology; Chemical properties; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; Dextroamphetamine - pharmacology; Dopamine - metabolism; Dopamine and cAMP-Regulated Phosphoprotein 32; Drugs; Frontal Lobe - drug effects; Frontal Lobe - metabolism; Gene expression regulation; Genes, fos; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Information Processing; Inhibition; LSD; LSD (Drug); Lysergic Acid Diethylamide; Lysergic Acid Diethylamide - pharmacology; Male; Medical sciences; Messenger RNA; Mice; Mice, Knockout; Motor Activity - drug effects; Narcotics; Nerve Tissue Proteins - metabolism; Neurons; Neuropharmacology; Pharmacology. Drug treatments; Phencyclidine; Phencyclidine - pharmacology; Phosphoprotein Phosphatases - antagonists & inhibitors; Phosphoproteins - metabolism; Phosphorylation; Physiological aspects; Physiological regulation; Protein Phosphatase 1; Proteins; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Receptors, Dopamine D1 - genetics; Receptors, Dopamine D1 - metabolism; Reflex, Startle - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Schizophrenia; Signal Transduction; Synaptic Transmission; United States; Vertebrata; Agonist; Mammalia; Mouse; CNS stimulant; Psychotropic; Dopamine receptor; Animal; Rodentia; Glutamate receptor; Antagonist; Serotonine receptor
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1089681

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 phosphoprotein 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.