Antidepressants elevate GDNF expression and release from C₆ glioma cells in a β-arrestin1-dependent, CREB interactive pathway

Int J Neuropsychopharmacol. 2011 Nov;14(10):1289-300. doi: 10.1017/S1461145710001550. Epub 2011 Jan 12.

Abstract

Glial cell line-derived neurotrophic factor (GDNF), essential for neuronal survival, plasticity and development, has been implicated in the mechanism of action of antidepressant drugs (ADs). β-arrestin1, a member of the arrestin protein family, was found to play a role in AD mechanism of action. The present study aimed at evaluating whether the effect of ADs on GDNF in C6 rat glioma cells is exerted through a β-arrestin1-dependent, CREB-interactive pathway. For chronic treatment, C6 rat glioma cells were treated for 3 d with different classes of ADs: imipramine - a non-selective monoamine reuptake inhibitor, citalopram - a serotonin selective reuptake inhibitor (SSRI) or desipramine - a norepinephrine selective reuptake inhibitor (NSRI) and compared to mood stabilizers (lithium and valproic acid) or to the antipsychotic haloperidol. Only ADs significantly elevated β-arrestin1 levels in the cytosol, while reducing phospho-β-arrestin1 levels in the cell nuclear fraction. ADs significantly increased both GDNF expression and release from the cells, but were unable to induce such effects in β-arrestin1 knock-down cells. Chronic AD treatment significantly increased CREB phosphorylation without altering the level of total CREB in the nuclear fraction of the cells. Moreover, treatment with ADs significantly increased β-arrestin1/CREB interaction. These findings support the involvement of β-arrestin1 in the mechanism of action of ADs. We suggest that following AD treatment, β-arrestin1 generates a transcription complex involving CREB essential for GDNF expression and release, thus enhancing GDNF's neuroprotective action that promotes cellular survival and plasticity when the survival and function of neurons is compromised as occurs in major depression.

Publication types

  • Comparative Study

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology
  • Animals
  • Antidepressive Agents / pharmacology*
  • Antimanic Agents / pharmacology
  • Antipsychotic Agents / pharmacology
  • Arrestins / genetics
  • Arrestins / metabolism*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Cell Line, Tumor
  • Citalopram / pharmacology
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Desipramine / pharmacology
  • Dose-Response Relationship, Drug
  • Glial Cell Line-Derived Neurotrophic Factor / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Haloperidol / pharmacology
  • Imipramine / pharmacology
  • Neurotransmitter Uptake Inhibitors / pharmacology*
  • Phosphorylation
  • RNA Interference
  • Rats
  • Serotonin Uptake Inhibitors / pharmacology
  • Signal Transduction / drug effects*
  • Transcription, Genetic / drug effects
  • Transfection
  • Up-Regulation
  • Valproic Acid / pharmacology
  • beta-Arrestins

Substances

  • Adrenergic Uptake Inhibitors
  • Antidepressive Agents
  • Antimanic Agents
  • Antipsychotic Agents
  • Arrestins
  • CREB1 protein, rat
  • Cyclic AMP Response Element-Binding Protein
  • Glial Cell Line-Derived Neurotrophic Factor
  • Neurotransmitter Uptake Inhibitors
  • Serotonin Uptake Inhibitors
  • beta-Arrestins
  • Citalopram
  • Valproic Acid
  • Haloperidol
  • Imipramine
  • Desipramine