PHARMACOLOGICAL INDUCTION OF RHYTHMICAL ACTIVITY AND PLATEAU ACTION-POTENTIALS IN UNMYELINATED AXONS

The physiological function of the axon is to conduct short all-or-none action potentials from their site of initiation (usually the cell bod y) to the synapse. To ensure this function, both passive and active bi ophysical properties of the axons are tuned very precisely, especially the voltage-dependent ionic conductances to sodium and potassium. Und er normal conditions, axons are not spontaneously active. Minor modifi cations of their ionic micro-environment or slight changes in the memb rane properties are however sufficient to induce rhythmical activity a nd modify the time course of the action potentials. These modification s can be induced by a variety of pharmacological agents. Some typical examples taken from original studies on invertebrate preparations are illustrated. The experiments were carried out on two axonal preparatio ns: the giant axon of the squid Loligo forbesi and the giant axon of t he cockroach Periplaneta americana. The axons were 'space-clamped' and studied under both current-clamp and voltage-clamp conditions. Voltag e-clamp experiments were used to dissect out the mechanisms underlying repetitive activity and to extract the relevant parameters. These par ameters were then used to rebuild the observed effects using an extend ed version of the Hodgkin and Huxley (1952, J Physiol (Lond) 117, 500- 544) formulation. One easy way to get repetitive firing in both prepar ations is to reduce potassium conductance. The effect of I-aminopyridi ne on squid axon is illustrated here, The experimental results, includ ing the occurrence of bursts of activity, can be described by adding a time- and voltage-dependent block of the potassium channels to the or iginal Hodgkin and Huxley (1952, J Physiol (Lond) 117, 500-544) model. Repetitive spike activity and plateau action potentials are also prod uced when the depolarising effect of the voltage-dependent potassium c urrent is counterbalanced by a maintained inward sodium current. This maintained sodium current can be due to several different mechanisms. This will be illustrated by five structurally unrelated molecules: two scorpion toxins, two insecticide molecules and one sea anemone toxin. One toxin purified from the venom of the scorpion Buthotus judaicus ( insect toxin 1) exerts its effects by shifting the sodium activation c urve towards more hyperpolarized potentials. Another toxin purified fr om the venom of another scorpion Androctonus australis (mammal toxin 1 ) modifies a significant proportion of normal (fast) sodium channels i nto slowly activating and inactivating sodium channels. The main effec t of the insecticide DDT is to maintain sodium channels in the 'open' configuration. Another insecticide molecule known to induce repetitive activity, S-bioallethrin, activates voltage-dependent sodium channels with slow activation and inactivation kinetics. The sea anemone toxin anthopleurin A, purified from the venom of Anthopleura xanthogrammica , delays inactivation of the sodium current without changing its activ ation kinetics. These examples show that minor modifications of the pr operties of the nerve membrane are sufficient to alter nerve Function. These deleterious effects will be amplified at the synapse through dr amatic changes in transmitter release and will lead eventually to disa strous alterations of brain function.