The sudden infant death syndrome (SIDS) is postulated to result from a failure of homeostatic responses to life-threatening challenges (e.g. asphyxia, hypercapnia) during sleep. The ventral medulla participates in sleep-related homeostatic responses, including chemoreception, arousal, airway reflex control, thermoregulation, respiratory drive, and blood pressure regulation, in part via serotonin and its receptors. The ventral medulla in humans contains the arcuate nucleus, in which we have shown isolated defects in muscarinic and kainate receptor binding in SIDS victims. We also have demonstrated that the arcuate nucleus is anatomically linked to the nucleus raphé obscurus, a medullary region with serotonergic neurons. We tested the hypothesis that serotonergic receptor binding is decreased in both the arcuate nucleus and nucleus raphé obscurus in SIDS victims. Using quantitative autoradiography, 3H-lysergic acid diethylamide (3H-LSD binding) to serotonergic receptors (5-HT1A-D and 5-HT2 subtypes) was measured blinded in 19 brainstem nuclei. Cases were classified as SIDS (n = 52), acute controls (infants who died suddenly and in whom a complete autopsy established a cause of death) (n = 15), or chronic cases with oxygenation disorders (n = 17). Serotonergic binding was significantly lowered in the SIDS victims compared with controls in the arcuate nucleus (SIDS, 6 +/- 1 fmol/mg tissue; acutes, 19 +/- 1; and chronics, 16 +/- 1; p = 0.0001) and n. raphé obscurus (SIDS, 28 +/- 3 fmol/mg tissue; acutes, 66 +/- 6; and chronics, 59 +/- 1; p = 0.0001). Binding, however, was also significantly lower (p < 0.05) in 4 other regions that are integral parts of the medullary raphé/serotonergic system, and/or are derived, like the arcuate nucleus and nucleus raphé obscurus, from the same embryonic anlage (rhombic lip). These data suggest that a larger neuronal network than the arcuate nucleus alone is involved in the pathogenesis of SIDS, that is, a network composed of inter-related serotonergic nuclei of the ventral medulla that are involved in homeostatic mechanisms, and/or are derived from a common embryonic anlage.

Muscarinic cholinergic activity in the human arcuate nucleus at the ventral medullary surface is postulated to be involved in cardiopulmonary control. A significant decrease in [3H]quinuclidinyl benzilate binding to muscarinic receptors in the arcuate nucleus is now shown to occur in sudden infant death syndrome (SIDS) infants, compared to infants dying acutely of known causes. In infants with chronic oxygenation abnormalities, binding is low in other nuclei, as well as in the arcuate nucleus. The binding deficit in the arcuate nucleus of SIDS infants might contribute to a failure of responses to cardiopulmonary challenges during sleep.

Maternal cigarette smoking during pregnancy has been shown to be a major risk factor for the sudden infant death syndrome (SIDS). We hypothesized that SIDS is associated with altered 3H-nicotine binding to nicotinic receptors in brainstem nuclei related to cardiorespiratory control and/or arousal. We analyzed 3H-nicotine binding in 14 regions in SIDS and control brainstems using quantitative tissue receptor autoradiography. Three groups were analyzed: SIDS (n = 42), acute controls (n = 15), and a chronic group with oxygenation disorders (n = 18). The arcuate nucleus, postulated to be important in cardiorespiratory control and abnormal in at least some SIDS victims, contained binding below the assay detection limits in all (SIDS and control) cases. We found no significant differences among the 3 groups in mean 3H-nicotine binding in the 14 brainstem sites analyzed. When a subset of the cases were stratified by the history of the presence or absence of maternal cigarette smoking during pregnancy, however, we found that there was no expected increase (upregulation) of nicotinic receptor binding in SIDS cases exposed to cigarette smoke in utero in 3 nuclei related to arousal or cardiorespiratory control. This finding raises the possibility that altered development of nicotinic receptors in brainstem cardiorespiratory and/or arousal circuits put at least some infants, i.e. those exposed to cigarette smoke in utero, at risk for SIDS, and underscores the need for further research into brainstem nicotinic receptors in SIDS in which detailed correlations with smoking history can be made.

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