title: Serotonin transporter occupancy in rats exposed to serotonin reuptake inhibitors in utero or via breast milk.
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.
authors.affiliation: Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Capello
authors.forename: Chase H
authors.initials: CH
authors.lastname: Bourke
authors.forename: James C
authors.initials: JC
authors.lastname: Ritchie
authors.forename: Zachary N
authors.initials: ZN
authors.lastname: Stowe
authors.forename: D Jeffrey
authors.initials: DJ
authors.lastname: Newport
authors.forename: Amanda
authors.initials: A
authors.lastname: Nemeroff
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owens
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000523:psychology; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism; D005473:Fluoxetine / Q000493:pharmacokinetics / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D015918:Infusion Pumps, Implantable; D008425:Maternal Behavior / Q000502:physiology; D008431:Maternal-Fetal Exchange; D008892:Milk / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D009048:Motor Skills / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D020318:Rats, Long-Evans; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D005473:Fluoxetine; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors