Additive and synergistic effects of fetal nicotine and dexamethasone exposure on cholinergic synaptic function in adolescence and adulthood: Implications for the adverse consequences of maternal smoking and pharmacotherapy of preterm delivery.
Maternal smoking contributes to preterm delivery; glucocorticoids are the consensus treatment for prematurity, thus producing fetal coexposure to nicotine and dexamethasone. We administered nicotine to pregnant rats throughout gestation at a dose (3 mg/kg/day) producing plasma levels typical of smokers. Later in gestation, animals received dexamethasone (0.2 mg/kg). We assessed developmental indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, evaluating brain regions possessing major ACh projections and cell bodies; we measured choline acetyltransferase activity, hemicholinium-3 binding to the presynaptic choline transporter and nicotinic ACh receptor binding. In general, nicotine and dexamethasone, alone or in combination, produced regionally-selective increases or decreases in choline acetyltransferase activity but larger, consistent elevations in hemicholinium-3 and nicotinic ACh receptor binding; the patterns were indicative of ACh synaptic hyperactivity. Superimposed on these overall effects, there were significant disparities in temporal and regional relationships among the different treatments, notably 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 ACh neuronal injury that then persists throughout the lifespan but rather, they alter the developmental trajectory of ACh function. Most importantly, the combined exposure to nicotine + dexamethasone elicited greater changes than either of the individual exposures, involving both additive and synergistic effects. Our results thus point to potentially worse neurobehavioral outcomes of the 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
Ryde
Ian T
IT
Seidler
Frederic J
FJ
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006426:Hemicholinium 3 / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D007752:Obstetric Labor, Premature / Q000188:drug therapy; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017729:Presynaptic Terminals / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism; D012907:Smoking; D013569:Synapses / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D005938:Glucocorticoids; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D011978:Receptors, Nicotinic; C075746:Slc6a8 protein, rat; D006426:Hemicholinium 3; D009538:Nicotine; D003907:Dexamethasone; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine