Mimicking maternal smoking and pharmacotherapy of preterm labor: interactions of fetal nicotine and dexamethasone on serotonin and dopamine synaptic function in adolescence and adulthood.
Fetal coexposure to nicotine and dexamethasone is common: maternal smoking increases the incidence of preterm delivery and glucocorticoids are the consensus treatment for prematurity. We gave pregnant rats 3mg/kg/day of nicotine throughout gestation, a regimen that reproduces smokers' plasma levels, and then on gestational days 17, 18 and 19, we administered 0.2mg/kg of dexamethasone. We evaluated developmental indices for serotonin (5HT) and dopamine synaptic function throughout adolescence, young adulthood and later adulthood, assessing the brain regions possessing major 5HT and dopamine projections and cell bodies. Males displayed persistent upregulation of 5HT(1A) and 5HT(2) receptors and the 5HT transporter, with a distinct hierarchy of effects: nicotine<dexamethasone<combined treatment. Females showed downregulation of the 5HT(1A) receptor with the same rank order; both sexes displayed presynaptic hyperactivity of 5HT and dopamine pathways as evidenced by increased neurotransmitter turnover. Superimposed on these overall effects, there were significant differences in temporal and regional relationships among the different treatments, often involving effects that emerged later in life, after a period of apparent normality. This indicates that nicotine and dexamethasone do not simply produce an initial neuronal injury that persists throughout the lifespan but rather, they alter the developmental trajectory of synaptic function. The fact that the combined treatment produced greater effects for many parameters points to potentially worse neurobehavioral outcomes after pharmacotherapy of preterm labor in the offspring of smokers.
Slotkin
Theodore A
TA
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Seidler
Frederic J
FJ
D000293:Adolescent; D000328:Adult; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D009538:Nicotine / Q000494:pharmacology*; D007752:Obstetric Labor, Premature / Q000188:drug therapy*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D012907:Smoking; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
D005938:Glucocorticoids; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D009538:Nicotine; D003907:Dexamethasone; D004298:Dopamine