title: The SSRI citalopram affects fetal thalamic axon responsiveness to netrin-1 in vitro independently of SERT antagonism.
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.
authors.affiliation: Zilkha Neurogenetic Institute and Department of Cell and Neurobiology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bonnin
authors.forename: Le
authors.initials: L
authors.lastname: Zhang
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
authors.forename: Pat
authors.initials: P
authors.lastname: Levitt
mesh_terms: D000818:Animals; D001369:Axons; D015283:Citalopram / Q000494:pharmacology*; D018920:Coculture Techniques; D005260:Female; D005333:Fetus; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000494:pharmacology*; D000075388:Netrin-1; D017374:Paroxetine / Q000494:pharmacology; D017480:Receptors, sigma / Q000819:agonists; D012701:Serotonin / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013788:Thalamus / Q000187:drug effects* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000494:pharmacology*; D000097605:Sigma-1 Receptor
chemical_list: D015283:Citalopram; D009414:Nerve Growth Factors; D000075388:Netrin-1; D017374:Paroxetine; D017480:Receptors, sigma; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D025521:Tumor Suppressor Proteins; D000097605:Sigma-1 Receptor; C000617353:Ntn1 protein, mouse; C493231:Slc6a4 protein, mouse