Inhibition of neuronal firing in murine striatal slices by cyclodiene insecticides is mediated by release of dopamine and not GABA antagonism

Abstract

This study investigated the effects of dieldrin and heptachlor epoxide, members of the cyclodiene class of insecticides, on neuronal firing in murine brain slices. The cyclodienes are environmentally persistent and human exposure to these compounds still occurs. Major physiological effects of cyclodienes include: (1) blockage of 3 GABA A receptors and (2) facilitation of neurotransmitter release with specificity for release of dopamine. Extracellular recordings were used to compare the effects of the cyclodienes to those of the prototypical GABA antagonist, picrotoxinin, on firing rates of striatal neurons. Recordings were made from cells that were inhibited by exogenously applied dopamine, which is an ideal neural substrate for differentiating effects on dopamine release from GABA antagonism. Low micromolar concentrations of cyclodiene caused depression of firing, inconsistent with GABA antagonism. Alternatively, application of picrotoxinin produced a consistent neuronal excitation in slices. The inhibitory action of dieldrin was blocked by the dopamine receptor antagonist fluphenazine, verifying the fact that cyclodiene-released dopamine was mediating the observed depression of striatal neurons. These results suggest that the ability of cyclodienes to evoke neurotransmitter release, especially dopamine, may significantly contribute to the neurotoxicity of these compounds, in vivo.