Metaldehyde Molluscicide Action in Mice: Distribution, Metabolism, and Possible Relation to GABAergic System

Abstract

Two proposed modes of toxic action of the molluscicide metaldehyde are considered here by studies in orally treated mice of symptomatology, acetaldehyde and metaldehyde concentrations in tissues, and characteristics of the γ-aminobutyric acid (GABA) receptor complex. An earlier proposal that metaldehyde-induced poisoning is due to acetaldehyde liberation is not supported by either their different symptomatology or tissue analyses. Unmetabolized metaldehyde is excreted to the extent of 8% and the urinary metabolites from [13C]metaldehyde and [13C]acetate are consistent with primary degradation of metaldehyde via acetaldehyde and acetate. Poisoning signs are initiated at ∼12 ppm metaldehyde in brain, progressing to tonic convulsions and death at ∼40 ppm and lessened by diazepam and phenobarbital without greatly altering the tissue levels of metaldehyde. Possible involvement of the GABAergic system in metaldehyde toxicity is suggested by the lowered levels of GABA in the brain of poisoned mice determined by (1) earlier chemical analysis of the whole brain (Homeida and Cooke,J. Vet. Pharmacol. Ther.5,77 (1982)) and (2) the presently observed reduced effect of endogenous inhibitors (primarily GABA) in preventing binding of [3H]ethynylbicycloorthobenzoate ([3H]EBOB) to brain membranes. Metaldehyde (1 mM) does not: (1) inhibit [3H]EBOB bindingin vitroat the noncompetitive blocker site, (2) alter the coupled effects on [3H]EBOB binding of GABA as an inhibitor (acting at the GABA recognition site) and the amidine steroid RU 5135 in reversing this inhibition (acting primarily as a competitive antagonist), or (3) inhibit glutamic acid decarboxylase activity. Thus, the toxicity of metaldehyde is not due to degradation to acetaldehyde but instead may result from disrupting the GABAergic system by a mechanism which remains to be determined.