Evidence from a variety of animal species suggests that neurotransmitters play roles in morphogenesis prior to development of neurotransmission. For example, studies in the chick embryo demonstrate sites of uptake and/or synthesis for serotonin (5-HT) and norepinephrine (NE) in the early neural tube and notochord, and drugs which interfere with the uptake, synthesis or metabolism of these substances produce malformations of the nervous system. In the mouse, such drugs cause similar malformations, but no studies have yet been conducted to determine whether 5-HT or NE sites exist in this or other mammalian species, which could provide a good model for studies of drug-induced malformations in the human. In preliminary studies, using whole embryo culture of mouse embryos, we have identified sites of 5-HT uptake and/or synthesis by incubation of embryos with 5-HT or precursors followed by immunocytochemical staining of fixed sections with an antiserum to 5-HT. Using this approach, we have localized 5-HT uptake sites in the developing heart, head ectoderm, epiphysis, mandibular and pharyngeal arches, palate, otocyst (ear), and hindgut underlying the caudal neural tube during closure. Using the whole embryo culture system, we propose to study these 5-HT sites in terms of 1) their developmental timecourse and pharmacologic characterization, and 2) as potential foci for teratogenic effects of 5-HT-interactive drugs. The possible morphogenetic roles of other neurotransmitters for which we have antisera (e.g., catecholamines and GABA) will also be examined using the same in vitro approach in which we will first explore sites of uptake and/or synthesis and then test appropriate drugs for related teratogenic effects. These studies should produce new information regarding roles for neurotransmitters in morphogenesis as well as providing valuable insights into possible site-specific malformations caused by psychoactive drugs taken by the pregnant woman.
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