The objective of the proposed research is to elucidate the molecular mechanisms by which pyrethroids exert their neurotoxicological effects in mammalian species. Specifically, these investigations will attempt to determine whether there are toxicologically relevant differences in the interaction of Type I vs Type II pyrethroids with the benzodiazepine-GABA receptor ionophore complex. Moreover, the effects of chronic exposure to pyrethroids on the characteristics and function of the GABA receptor-ionophore complex and related sites will be determined. The reported interactions of Type II pyrethroids with the GABA- gated chloride channel will be characterized in vitro and in vivo using (35S)t-butylbicyclophosphorothionate to label this ion channel. The interaction of Type I and Type II pyrethroids with the """"""""peripheral-type"""""""" benzodiazepine receptor will also be investigated using (3H)PK 11195 as a radioligand probe for this recognition site in both in vitro and in vivo studies. The hypothesis that a novel """"""""peripheral type"""""""" benzodiazine receptor may be functionally coupled to the GABA-gated chloride channel will be evaluated using pyrethroids as probes in the study of the allosteric modulation of (35S)-t-butylbicyclophosporothionate binding. The potential influence of chronic exposure to pyrethroids on the coupling efficiency between the chloride ion channel and GABA and benzodiazepine receptors will be assessed. The functional consequences of pyrethroid occupancy of these receptor sites will be examined by characterization of the proconvulsant actions of Type I and Type II pyrethroids against seizures elicited from an epileptogenic site in the prepiriform cortex. Correlations between receptor site occupancy in vivo and pyrethroid modulation of seizure susceptibility will be obtained. The effects of pyrethroids on GABA-gated chloride influx will be investigated in intact neurons and in synaptoneurosome preparations. Thus, both pyrethroid-neuroreceptor interaction as well as the functional consequences of activation of various ligand binding sites associated with the GABA/benzodiazepine receptor- ionophore complex will be ascertained. The results of these investigations will further our understanding of molecular mechanisms operative in the pyrethroid modulation of seizure susceptibility. The ability of PK 11195 to antagonize the proconvulsant effects of pyrethroids will be further characterized. Considered together, these results may have important clinical implications concerning potential neurotoxic sequelae of pyrethroid exposure.
| Eshleman, A J; Murray, T F (1991) Pyrethroid insecticides indirectly inhibit GABA-dependent 36Cl- influx in synaptoneurosomes from the trout brain. Neuropharmacology 30:1333-41 |
| Eshleman, A J; Murray, T F (1990) Dependence on gamma-aminobutyric acid of pyrethroid and 4'-chlorodiazepam modulation of the binding of t-[35S]butylbicyclophosphorothionate in piscine brain. Neuropharmacology 29:641-8 |
