Regional mirex distribution and its effects on gamma-aminobutyric acid and flunitrazepam binding in mouse brains.
Following ip injection of [14C]mirex, its regional distribution was studied parallel to its in vitro effects on [3H]-gamma-aminobutyric acid (GABA) and [3H]flunitrazepam (FNZ) binding to, and [3H]GABA release from, synaptosomes of various mouse brain regions, in order to determine the relationship between relative mirex distribution and its neurotoxic effects mediated through the GABA receptor-ionophore complex. The pattern of mirex uptake into cerebral cortex (CC), brainstem (BS), and cerebellum (CB) showed an initial linear dose-dependent uptake, followed by a decline at higher concentration. The Vmax and Km values determined for the linear mirex uptake phase indicated varied affinities by brain regions, CB and BS being more susceptible to mirex uptake than CC. Both synaptosomal GABA binding and FNZ binding were significantly reduced by mirex in the order of BS approximately equal to CB greater than CC for GABA, and BS approximately equal to CC greater than CB for FNZ. However, mirex lacked any significant effect on the Ca2+-dependent, K+-stimulated release of GABA from radio-prelabeled synaptosomes. While the data indicate no significant differences between brain regions in mirex uptake, they suggest that regional specificities do exist with respect to the inhibition caused by mirex on GABA and FNZ binding to synaptosomes. Unlike the major effects of chlordecone (an analog of mirex) on the dopaminergic system, mirex seems to be primarily neurotoxic through its more specific interaction with the GABA and FNZ binding sites.
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000378:metabolism*; D004347:Drug Interactions; D005445:Flunitrazepam / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007306:Insecticides / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D051379:Mice; D008917:Mirex / Q000378:metabolism* / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002250:Carbon Radioisotopes; D007306:Insecticides; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; D008917:Mirex