ABSTRACT
The pathophysiology of depression remains enigmatic, although abnormalities in serotonin signaling have been implicated. We have found that the serotonin 1B receptor [5-hydroxytryptamine (5-HT1B) receptor] interacts with p11. p11 increases localization of 5-HT1B receptors at the cell surface. p11 is increased in rodent brains by antidepressants or electroconvulsive therapy, but decreased in an animal model of depression and in brain tissue from depressed patients. Overexpression of p11 increases 5-HT1B receptor function in cells and recapitulates certain behaviors seen after antidepressant treatment in mice. p11 knockout mice exhibit a depression-like phenotype and have reduced responsiveness to 5-HT1B receptor agonists and reduced behavioral reactions to an antidepressant.
Subject(s)
Annexin A2/metabolism , Depression/metabolism , Receptor, Serotonin, 5-HT1B/metabolism , S100 Proteins/metabolism , Adult , Aged , Animals , Annexin A2/genetics , Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Brain/drug effects , Brain/metabolism , Cell Membrane/metabolism , Depression/genetics , Electroconvulsive Therapy , Female , Humans , Male , Mice , Mice, Knockout , Mice, Transgenic , Middle Aged , Neurons/metabolism , Rats , S100 Proteins/genetics , Serotonin/metabolism , Serotonin/physiology , Signal Transduction , Two-Hybrid System TechniquesABSTRACT
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.