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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 8
- Comparative and Interactive Human Psychopharmacologic Effects of Ketamine and Amphetamine Archives of General Psychiatry September 1, 2005
- Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways Current Topics in Behavioral Neurosciences 2017
- Interaction between LSD and dopamine D2/3 binding sites in pig brain Synapse 2005
- Psychotomimetic effects of PCP, LSD, and Ecstasy: pharmacological models of schizophrenia? Cambridge University Press eBooks February 4, 2010
- GLT-1 expression and Glu uptake in rat cerebral cortex are increased by phencyclidine. Glia September 2008
and 3 more in the library
Cites 3
- Study of a New Schizophrenomimetic Drug—Sernyl Archives of Neurology And Psychiatry March 1, 1959
- Advances and Pathophysiological Models of Hallucinogenic Drug Actions in Humans: A Preamble to Schizophrenia Research Pharmacopsychiatry July 1, 1998
- Some Serotoninlike Activities of Lysergic Acid Diethylamide Science July 20, 1956