Antidepressants elevate GDNF expression and release from C 6 glioma cells in a β-arrestin1-dependent, CREB interactive pathway

Moran Golan, Gabriel Schreiber, Sofia Avissar

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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.

Original languageEnglish
Pages (from-to)1289-1300
Number of pages12
JournalInternational Journal of Neuropsychopharmacology
Issue number10
StatePublished - 1 Nov 2011


  • Antidepressants
  • CREB
  • GDNF
  • glial cells
  • β-arrestin1

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)


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