The development of nicotinic receptors in the human medulla oblongata: inter-relationship with the serotonergic system.
Maternal cigarette smoking during pregnancy adversely affects fetal development and increases the risk for the sudden infant death syndrome (SIDS). In SIDS we have reported abnormalities in the medullary serotonergic (5-HT) system, which is vital for homeostatic control. In this study we analyzed the inter-relationship between nicotinic receptors (nAChRs), to which nicotine in cigarette smoke bind, and the medullary 5-HT system in the human fetus and infant as a step towards determining the mechanisms whereby smoking increases SIDS risk in infants with 5-HT defects. Immunohistochemistry for the alpha4 nAChR subunit and 5-HT neurons was applied in fetal and infant medullae (15-92 postconceptional weeks, n=9). The distribution of different nAChRs was determined from 39-82 postconceptional weeks (n=5) using tissue autoradiography for 3H-nicotine, 3H-epibatidine, 3H-cytisine, and 125I-bungarotoxin; the findings were compared to laboratory 5-HT1A and 5-HT transporter binding data, and 5-HT neuronal density. Alpha4 immunoreactivity was ubiquitously expressed in medullary nuclei related to homeostatic functions from 15 weeks on, including rhombic lip germinal cells. At all ages, alpha4 co-localized with 5-HT neurons, indicating a potential site of interaction whereby exogenous nicotine may adversely affect 5-HT neuronal development and function. Binding for heteromeric nAChRs was highest in the inferior olive, and for homomeric nAChRs, in the vagal complex. In the paragigantocellularis lateralis, 5-HT1A receptor binding simultaneously increased as alpha7 binding decreased across infancy. This study indicates parallel dynamic and complex changes in the medullary nicotinic and 5-HT systems throughout early life, i.e., the period of risk for SIDS.
Duncan
Jhodie R
JR
Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA. jhodie.duncan@childrens.harvard.edu
Paterson
David S
DS
Kinney
Hannah C
HC
D001667:Binding, Competitive / Q000502:physiology; D001931:Brain Mapping; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008526:Medulla Oblongata / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D013398:Sudden Infant Death
D011978:Receptors, Nicotinic; D050486:Serotonin Plasma Membrane Transport Proteins; C403531:nicotinic receptor alpha4beta2; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin