The SSRI citalopram affects fetal thalamic axon responsiveness to netrin-1 in vitro independently of SERT antagonism

Neuropsychopharmacology. 2012 Jul;37(8):1879-84. doi: 10.1038/npp.2012.35. Epub 2012 Mar 14.

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) signaling is thought to modulate nervous system development. Genetic and pharmacological studies support the idea that altered 5-HT signaling during development can have enduring consequences on brain function and behavior. Recently, we discovered that 5-HT can modulate thalamic axon guidance in vitro and in vivo. Embryonic thalamic axons transiently express the 5-HT transporter (SERT; Slc6a4) and accumulate 5-HT, suggesting that the SERT activity of these axons may regulate 5-HT-modulated guidance cues. We tested whether pharmacologically blocking SERT using selective 5-HT reuptake inhibitors (SSRIs) would impact the action of 5-HT on thalamic axon responses to netrin-1 in vitro. Surprisingly, we observed that two high-affinity SSRIs, racemic citalopram ((RS)-CIT) and paroxetine, affect the outgrowth of embryonic thalamic axons, but differ with respect to their dependence on SERT blockade. Using a recently developed 'citalopram insensitive' transgenic mouse line and in vitro pharmacology, we show that the effect of (RS)-CIT effect is SERT independent, but rather arises from R-CIT activation of the orphan sigma-1 receptor(σ1, Oprs1). Our results reveal a novel σ1 activity in modulating axon guidance and a 5-HT independent action of a widely prescribed SSRI. By extension, (RS)-CIT and possibly other structurally similar SSRIs may have other off-target actions that can impact neural development and contribute to therapeutic efficacy or side effects.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axons
  • Citalopram / pharmacology*
  • Coculture Techniques
  • Female
  • Fetus
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Nerve Growth Factors / pharmacology*
  • Netrin-1
  • Paroxetine / pharmacology
  • Receptors, sigma / agonists
  • Serotonin / pharmacology
  • Serotonin Plasma Membrane Transport Proteins / genetics
  • Serotonin Uptake Inhibitors / pharmacology*
  • Thalamus / drug effects*
  • Thalamus / physiology
  • Tumor Suppressor Proteins / pharmacology*

Substances

  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Receptors, sigma
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Slc6a4 protein, mouse
  • Tumor Suppressor Proteins
  • sigma-1 receptor
  • Citalopram
  • Netrin-1
  • Serotonin
  • Paroxetine