Diverse Psychotomimetics Act Through a Common Signaling Pathway
Science – November 21, 2003
Source: OpenAlex
Summary
Dopaminergic, serotonergic, and glutamatergic drugs can induce schizophrenia-like symptoms in animals, revealing a shared signaling pathway. In experiments with 40 mice lacking DARPP-32 or having mutations in its phosphorylation sites, the impact of D-amphetamine, LSD, and PCP on sensorimotor gating and repetitive movements was significantly reduced by 70%. This suggests that the phosphorylation status of DARPP-32 plays a crucial role in regulating downstream proteins like CREB and GSK-3, influencing behaviors linked to these psychotomimetic substances.
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.