Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome

Abstract

During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to fivefold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT(1A) receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors.

The Alteration of Neonatal Raphe Neurons by Prenatal–Perinatal Nicotine. Meaning for Sudden Infant Death Syndrome

“…Upregulation of 5-HT 1A Rs, similar to that reported by us, has been observed in rats (46) and in fetal nonhuman primates after chronic prenatal nicotine administration (25). The same changes have also been observed in offspring from pregnant Rhesus monkeys exposed to environmental tobacco smoke during gestation and for up to 3 months postnatally (26).…”

“…In fact, prenatalperinatal nicotine exposure causes hypoventilation (19,20), increased apnea periods during normoxia in mice and rats (21), reduction of hypercarbia-and hypoxiainduced ventilatory chemoreflexes in mice (19), rats (20,22), and sleeping lambs (23), reduction of autoresuscitation from primary apnea in rats (24), and delays in the hypoxiainduced awakening response in lambs (23). In the serotonergic system, prenatal nicotine increases serotonin 5-HT 1A R binding in the ROb of baboon fetuses (25) as perinatal tobacco exposure does in the cerebral cortex of rhesus monkeys (26). Prenatal nicotine elevates both concentration and turnover of serotonin in the brainstem of rhesus monkey fetuses (27).…”

Proposal for mechanisms of protection of supine sleep against sudden infant death syndrome: an integrated mechanism review

“…Based on extrapolations by this author (almost all cases show a defect, none yet found in controls), perhaps a 2/1,000 incidence of the defect with a 50% lethality (1/1,000 SIDS rate) has been modified by the "Back to Sleep" campaign from 1.2 to the current level of 0.6/1,000 in the USA (2). There may also be increasing allostatic load over time (35), as well as known risk factors such as nicotine (54), increasing the severity of the defect, as evidenced by further reduced serotonin gene expression in older SIDS cases (76). This is consistent also with the findings of multiple risk factors (acting as contributors to allostatic load) in the majority of SIDS cases.…”

Effects of postnatal environmental tobacco smoke on non-nutritive swallowing-breathing coordination in newborn lambs

“…Examples include anomalies in nicotinergic, GABAergic and serotonergic receptors (Duncan et al, 2009) …”