Selective location of acceptors for botulinum neurotoxin A in the central and peripheral nervous systems

The main site of action for botulinum neurotoxin is cholinergic motor nerve terminals where specific acceptors concentrate the toxin on the cell surface, thereby facilitating its internalization and inactivation of a component essential for transmitter release. In this study, the interaction in vitro of [125I]botulinum neurotoxin type A with central and peripheral nerve terminals of different types was investigated using Ultrofilm and electron-microscope autoradiography. It was found that: (i) The neurotoxin binds to synapse-rich areas of rat brain, particularly in the hippocampus and cerebellum; identity of the neuron types labelled is unclear although cholinergic nerves seem to be labelled, perhaps not exclusively, in many areas. (ii) Toxin uptake at central nerve terminals appears to be minimal and its penetration into intact brain slices is restricted; this may account for the toxin's lower central toxicity. (iii) Selective labelling of cholinergic nerves but not purinergic, peptidergic or adrenergic nerve terminals in mouse ileum suggests that the toxin may be a specific marker for cholinergic nerves in the periphery. Based on these localization studies and published pharmacological observations, it is concluded that efficient toxin-induced blockade of neurotransmission depends on the presence of specific acceptors of high affinity for the toxin and of an effective neuronal uptake mechanism. Inhibition of the release of numerous transmitters from different kinds of nerve terminals lacking one of these features can be produced by high toxin concentrations when uptake occurs via low affinity acceptors or by non-specific means. Notably, this widespread action of the toxin indicates the occurrence of a common intracellular target in several, possibly all, nerve types.