COMPARISON OF NICOTINIC RECEPTOR-BINDING AND BIOTRANSFORMATION OF CONIINE IN THE RAT AND CHICK

Coniine, an alkaloid from Conium maculatum (poison hemlock), is a know n teratogen in many domestic species with maternal ingestion resulting in arthrogryposis of the offspring. We have previously shown that rat s are not susceptible and rabbits only weakly susceptible to coniine-i nduced arthrogryposis. However, the chick embryo does provide a reprod ucible laboratory animal model of coniine-induced teratogenesis. The r eason for this cross-species variation is unknown. The purpose of this study was to evaluate coniine binding to nicotinic receptors and to m easure coniine metabolism in vitro between susceptible and non-suscept ible species. Using the chick model, neither the peripheral nicotinic receptor antagonist d-tubocurarine chloride nor the central nicotinic receptor antagonist trimethaphan camsylate blocked the teratogenesis o r lethality of 1.5% coniine (50 mu 1/egg). Trimethaphan camsylate enha nced coniine-induced lethality in a dose- dependent manner. Neither ni cotinic receptor blocker prevented nicotine sulfate-induced malformati ons but d-tubocurarine chloride did block lethality in a dose-dependen t manner. Competition by coniine for [I-125]-alpha-bungarotoxin to nic otinic receptors isolated from adult rat diaphragm and chick thigh mus cle and competition by coniine for [H-3]-cytisine to receptors from ra t and chick brain were used to assess coniine binding to nicotinic rec eptors. The IC50 for coniine in rat diaphragm was 314 mu M while that for chick leg muscle was 70 mu M. For neuronal nicotinic receptors, th e IC(50)s of coniine for maternal rat brain, fetal rat brain, and chic k brain were 1100 mu M, 820 mu M, and 270 mu M, respectively. There we re no differences in coniine biotransformation in vitro by microsomes from rat or chick livers. Differences in apparent affinity of coniine for nicotinic receptors or differences in the quantity of the nicotini c receptor between the rat and chick may explain, in part, the differe nces in susceptibility of coniine-induced teratogenesis between these two species.