EARLY DEVELOPMENTAL-CHANGES IN H-3! NICOTINE BINDING IN THE HUMAN BRAIN-STEM

Little is known about the developmental profile of nicotinic cholinerg ic receptors in the developing human brain, despite the potential impo rtance of such information in understanding the pathogenesis of neurol ogical abnormalities or increased risk for the sudden infant death syn drome in offspring exposed to nicotine in utero. In this study, we det ermined the distribution of H-3!nicotine binding in the developing hu man brainstem by quantitative tissue autoradiography. In midgestationa l fetuses, H-3!nicotine binding sites were heavily concentrated in te gmental nuclei related to cardiopulmonary integration, arousal, attent ion, rapid eye movement sleep, and somatic motor control. Over the las t half of gestation, H-3!nicotine binding decreased 60-70% in the teg mental nuclei, with a significant difference in binding between midges tation and early infancy. In contrast, there was essentially no change in H-3!nicotine binding in the major cerebellar-relay nuclei (princi pal inferior olive and griseum pontis) between the same time-points. T ritium quenching by increasing lipid (myelin) content in tissue sectio ns did not account for the decreases in H-3!nicotine binding in tegme ntal nuclei. Based upon the high levels of H-3!nicotine binding at mi dgestation, combined with experimental data demonstrating trophic prop erties for acetylcholine, we postulate that nAChRs play a role in the development of the brainstem tegmentum during this period, and that on ce this role is fulfilled, nicotinic cholinergic binding decreases and remains low thereafter. Alternatively, nicotinic cholinergic receptor s may be critical for other developmentally related functions and/or n eurotransmission in the brainstem tegmentum at midgestation. The high levels of H-3!nicotine binding in the brainstem tegmentum at midgesta tion and its rapidly changing profile over late gestation further sugg est that mid-to-late gestation is a developmental period during which this region is likely to be most vulnerable to the harmful effects of nicotine in maternal cigarette smoke. The baseline information provide d in this study is potentially relevant towards understanding attentio n deficits and risk for the sudden infant death syndrome in offspring exposed to cigarette smoke in utero.