Role of neurotransmitters in palate development and teratologic implications.
It is hypothesized that neuropharmacologic agents are more teratogenic to humans. Since many neuropharmacologic agents function through neurotransmitter mechanisms, then neurotransmitters should function to regulate embryonic development. Evidence has been obtained that neurotransmitters do indeed function as biological signals in palate development. It has been shown that palate reorientation is modulated by neurotransmitters with a wide range of diversity, similar to the CNS. Thus serotonin and acetylcholine stimulate and GABA inhibits the reorientation process. Spatial diversity is also observed: serotonin functions at the anterior and acetylcholine at the posterior end, and GABA functions more efficiently at either end in different inbred strains. Many criteria for functioning neurotransmitters have been obtained. Both serotonin and GABA have been measured in the palate and developmental changes observed. Physiologic responses to serotonin have been monitored. Serotonin has been shown to stimulate palate cell motility as well as protein carboxyl methylation and cyclic GMP. The serotonin effects on protein carboxyl methylation and cyclic GMP could function to stimulate palate reorientation by modulating cell contractility and protein secretion. Further support for the hypothesis that neuropharmacologic agents could be teratogenic by perturbation of neurotransmitter mechanisms comes from studying GABA and diazepam. Evidence has been obtained that diazepam induces cleft palate by mimicking GABA in a functional GABAergic system in palate development. A significant finding is that genetic differences in both diazepam teratogenesis and in a GABAergic system have been observed. Comparing the SWV and AJ strains, the SWV mouse showed (1) a greater sensitivity to diazepam-induced cleft palate, (2) a greater sensitivity to GABA and diazepam inhibition of palate reorientation in embryo culture, (3) a greater concentration of palatal GABA and (4) a more efficient GABA uptake system. These results are suggestive that diazepam may be more teratogenic in individuals of both the mouse and human who possess a more developed GABAergic mechanism. If such a result would obtain in the human, these genotypic differences in GABA would probably not influence the individual to a significant degree in most situations, except for the pregnant woman being at high risk when treated with diazepam.
Zimmerman
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D000014:Abnormalities, Drug-Induced / Q000196:embryology*; D000818:Animals; D001693:Biological Transport, Active; D002972:Cleft Palate / Q000139:chemically induced* / Q000196:embryology; D003975:Diazepam / Q000633:toxicity; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D009432:Neural Crest / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors / Q000502:physiology*; D010159:Palate / Q000196:embryology*; D011247:Pregnancy; D012701:Serotonin / Q000502:physiology; D013723:Teratogens / Q000633:toxicity*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018377:Neurotransmitter Agents; D013723:Teratogens; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; D003975:Diazepam