Differential Actions of Fipronil and Dieldrin Insecticides on GABA-Gated Chloride Channels in Cockroach Neurons

• Published in: The Journal of pharmacology and experimental therapeutics 2003-09, Vol.306 (3), p.914-924
• Main Authors: Zhao, Xilong, Salgado, Vincent L, Yeh, Jay Z, Narahashi, Toshio
• Format: Article
• Language: English
• Subjects: Animals; Chloride Channels - drug effects; Chloride Channels - physiology; Cockroaches; Dieldrin - toxicity; gamma-Aminobutyric Acid - metabolism; Insecticides - toxicity; Neurons - drug effects; Neurons - physiology; Pyrazoles - toxicity; Receptors, GABA - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.051839

Fipronil and dieldrin are known to inhibit GABA receptors in both mammals and insects. However, the mechanism of selective toxicity of these insecticides between mammals and insects remains to be seen. One possible mechanism is that insect GABA receptors are more sensitive than mammalian GABA A receptors to fipronil and dieldrin. We examined differential actions of fipronil and dieldrin on GABA-gated chloride channels in insects and compared them with the data on mammalian GABA A receptors. Neurons were acutely dissociated from the American cockroach thoracic ganglia, and currents evoked by GABA were recorded by the whole-cell patch-clamp technique. GABA-evoked currents were carried by chloride ions, blocked by picrotoxinin, but not by bicuculline. Fipronil inhibited GABA currents with an IC 50 value of 28 nM, whereas dieldrin exhibited a dual action potentiation with an EC 50 value of 4 nM followed by inhibition with an IC 50 value of 16 nM. Fipronil and dieldrin acted on the resting receptor at comparable rates, whereas fipronil blocked the activated receptor 10 times faster than dieldrin. Fipronil inhibition was partially reversible, whereas dieldrin inhibition was irreversible. Fipronil was 59 times more potent on cockroach GABA receptors than on rat GABA A receptors. However, the potentiating and inhibitory potencies of dieldrin in cockroach GABA receptors were comparable with those in rat GABA A receptors. It was concluded that the higher toxicity of fipronil in insects than in mammals is due partially to the higher sensitivity of GABA receptors. The mechanism of dieldrin's selective toxicity must lie in factors other than the sensitivity of GABA receptors.