Serotonin transporter occupancy in rats exposed to serotonin reuptake inhibitors in utero or via breast milk

Catherine F. Capello, Chase H. Bourke, James C. Ritchie, Zachary N. Stowe, D. Jeffrey Newport, Amanda Nemeroff, Michael J. Owens

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Rigorous data regarding fetal central nervous system (CNS) exposure after antidepressant exposure are sparse. The magnitude of serotonin reuptake inhibitor (SRI) CNS exposure was measured in three groups of rats using ex vivo autoradiography of the serotonin transporter (SERT): 1) in utero, 2) postnatal clearance after birth, and 3) exposure through lactation. Rats were exposed to one of five SRI-type antidepressants (escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine) administered continuously via osmotic minipumps to pregnant or nursing dams. Dam dosing was adjusted to reflect the 50th and 85th percentiles of serum concentrations observed in pregnant women. Embryonic day 21 rat pups exposed in utero exhibited >80% SERT occupancy in brain tissue, which is equivalent to that of the pregnant dam and similar to that reported for human pharmacotherapy. Venlafaxine was the exception with occupancies ranging from 61 to 92% across different litters. The magnitude of SERT occupancy is essentially equivalent between dams and fetuses. By postnatal day 4, high SERT occupancy was observed only in fluoxetine-exposed pups (41-92% occupancy). Significantly less, but measurable, exposure occurred via breast milk exposure even in the absence of detectable drug concentrations in nursing pup sera. Pups exposed to SRIs via breast milk for 3 or 7 days exhibited varying SERT occupancies (0-57% depending on the individual medication and dam dose). These data highlight the need for animal modeling of fetal and nursing infant drug exposure using clinically meaningful dosing strategies and appropriate CNS measures to develop rational treatment guidelines that systematically minimize fetal and neonatal medication exposure in humans.

Original languageEnglish (US)
Pages (from-to)275-285
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume339
Issue number1
DOIs
StatePublished - Oct 1 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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