Spinal motoneurons (MNs) in the chick embryo undergo programmed cell death 
coincident with the establishment of nerve-muscle connections and the onset of 
synaptic transmission at the neuromuscular junction. Chronic treatment of 
embryos during this period with nicotinic acetylcholine receptor 
(nAChR)-blocking agents [e.g., curare or alpha-bungarotoxin (alpha-BTX)] 
prevents the death of MNs. Although this rescue effect has been attributed 
previously to a peripheral site of action of the nAChR-blocking agents at the 
neuromuscular junction (NMJ), because nAChRs are expressed in both muscle and 
spinal cord, it has been suggested that the rescue effect may, in fact, be 
mediated by a direct central action of nAChR antagonists. By using a variety of 
different nAChR-blocking agents that target specific muscle or neuronal nAChR 
subunits, we find that only those agents that act on muscle-type receptors block 
neuromuscular activity and rescue MNs. However, paralytic, muscular dysgenic 
mutant chick embryos also exhibit significant increases in MN survival that can 
be further enhanced by treatment with curare or alpha-BTX, suggesting that 
muscle paralysis may not be the sole factor involved in MN survival. Taken 
together, the data presented here support the argument that, in vivo, nAChR 
antagonists promote the survival of spinal MNs primarily by acting peripherally 
at the NMJ to inhibit synaptic transmission and reduce or block muscle activity. 
Although a central action of these agents involving direct perturbations of MN 
activity may also play a contributory role, further studies are needed to 
determine more precisely the relative roles of central versus peripheral sites 
of action in MN rescue.