THE EFFECTS OF PESTICIDES, BREVETOXIN-B, AND THE CARDIOTONIC DRUG DPI-201-106 ON RELEASE OF ACETYLCHOLINE FROM INSECT CENTRAL NERVE-TERMINALS

Selected ion channel modulators (including pesticides, naturally occuring neurotoxins, and the cardiotonic drug DPI 201 106) were examined for their ability to affect acetylcholine release in a synaptosomal fraction isolated from the central nervous system of Acheta domesticus. Release elicited by the sodium channel activator veratridine was (i) inhibited by nanomolar concentrations of tetrodotoxin, RH3421, RH5529, and DPI 201 106; (ii) strongly enhanced by other sodium channel activators such as brevetoxin and (1R,αS) enantiomers of cypermethrin, and (iii) unaffected or marginally inhibited by the chloride channel blockers γ-hexachlorocyclohexane, dieldrin, and picrotoxinin. The chloride channel activator ivermectin caused release of acetylcholine at low concentrations (EC50 = 20 nM). This response was (i) effectively inhibited by submicromolar concentrations of α-hexachlorocyclohexane, dieldrin and picrotoxinin; (ii) partially inhibited by 1R,αS and 1S,αR enantiomers of cypermethrin and RH3421 and the R isomer of DPI 201 106; and (iii) unaffected by micromolar concentrations of tetrodotoxin, the S isomer of DPI 201 106, RH 5529 and brevetoxin B. On the basis of this investigation we conclude that those neurotoxins which promote sodium or chloride channel activation are capable of marked stimulatory effects on transmitter release. The pharmacological profiles of the inhibitors on evoked release accord well with their known mechanisms of action; however, no evidence was found for a direct enhancement of acetylcholine release with γ-hexachlorocyclohexane or dieldrin. © 1991.