Diverse Psychotomimetics Act Through a Common Signaling Pathway
Per Svenningsson, Eleni T. Tzavara, Robert Carruthers, Ilan Rachleff, Sigrid Wattler, Michael Nehls, David L. Mckinzie, Allen A. Fienberg, George G. Nomikos, Paul Greengard
Science November 21, 2003 DOI: 10.1126/science.1089681 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with genetically modified mice Peer reviewed |
|---|---|
| Population | Mice with genetic deletion or point mutations of DARPP-32 |
| Interventions | D-amphetamine LSD PCP |
| Topics | Serotonin |
| Keywords | Creb Amphetamine Protein kinase a Cyclic adenosine monophosphate Phosphorylation Dopaminergic pathways Signal transduction Ventral tegmental area Dopamine receptor Cell biology Pharmacology |
| Citations | 312 |
| Key findings | DARPP-32 is a common signaling mediator for psychotomimetic effects of dopaminergic, serotonergic, and glutamatergic drugs. |
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.