3-DIMENSIONAL DISTRIBUTION OF [H-3] QUINUCLIDINYL BENZILATE BINDING TO MUSCARINIC CHOLINERGIC RECEPTORS IN THE DEVELOPING HUMAN BRAIN-STEM

Acetylcholine has been implicated in brainstem mechanisms of cardiac a nd ventilatory control, arousal, rapid eye movement (REM) sleep, and c ranial nerve motor activity. Virtually nothing is known about the deve lopmental profiles of cholinergic perikarya, fibers, terminals, and/or receptors in the brainstems of human fetuses and infants. This study provides baseline information about the quantitative distribution of m uscarinic cholinergic receptors in fetal and infant brainstems. Brains tem sections were analyzed from 6 fetuses (median age: 21.5 postconcep tional weeks), 4 premature infants (median age: 26 postconceptional we eks), and 11 infants (median age: 53 postconceptional weeks). One chil d and three adult brainstems were examined as indices of maturity for comparison. The postmortem interval in all cases was less than or equa l to 24 hours (median: 10 hours). Muscarinic receptors were localized by autoradiographic methods with the radiolabeled antagonist [H-3]quin uclidinyl benzilate ([H-3]QNB). Computer-based methods permitted quant itation of [H-3]QNB binding in specific nuclei and three-dimensional r econstructions of binding patterns. By midgestation, muscarinic cholin ergic receptor binding is already present and regionally distributed, with the highest binding levels in the interpeduncular nucleus, inferi or colliculus, griseum pontis, nucleus of the solitary tract, motor cr anial nerve nuclei, and reticular formation. During the last half of g estation, [H-3]QNB binding decreases in most, but not all, of the nucl ei sampled. The most substantial decline occurs in the reticular forma tion of the medulla and pens, a change that is not fully explained by progressive myelination and lipid quenching. Binding levels remain ess entially constant in the inferior olive and griseum pontis. Around the time of birth or shortly thereafter, the relative distribution of bin ding becomes similar to that in the adult; with the highest levels in the interpeduncular nucleus and griseum pontis, although binding level s are higher overall in the infant. In the rostral pontine reticular f ormation, paramedian bands of high muscarinic binding are present whic h do not correspond to a cytoarchitectonically defined nucleus. By ana logy to animal studies, these bands may comprise a major cholinorecept ive region of the human rostral pontine reticular formation involved i n REM sleep. In the human interpeduncular nucleus in all age periods e xamined, muscarinic binding localizes to the lateral portions bilatera lly, indicative of a heterogeneous chemoarchitecture. Muscarinic bindi ng is high in the arcuate nucleus, a component of the putative respira tory chemosensitive fields along the ventral surface of the infant med ulla. This observation is consistent with the known effects of muscari nic agents on chemosensitivity and ventilatory responses applied to th e ventral medullary surface in animal models. The nonuniform distribut ion of muscarinic binding in the caudorostral plane in individual brai nstem nuclei, as illustrated by three-dimensional reconstructions, und erscores the need for rigorous sampling at precisely matched levels in quantitative studies. This study provides basic information toward un derstanding the neurochemical basis of brainstem disorders involving d ysfunction of autonomic and ventilatory control, arousal, and REM slee p in preterm and full-term newborns and infants and for developing cho linergic drugs for such disorders in the pediatric population. (C) 199 5 Wiley-Liss, Inc.