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.
Svenningsson
Per
P
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021, USA.
Tzavara
Eleni T
ET
Carruthers
Robert
R
Rachleff
Ilan
I
Wattler
Sigrid
S
Nehls
Michael
M
McKinzie
David L
DL
Fienberg
Allen A
AA
Nomikos
George G
GG
Greengard
Paul
P
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
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