endrin and picrotoxinin

1. In assays of 36Cl- uptake into mouse brain vesicles, 100 microM GABA markedly increased both the initial rate of 36Cl- uptake and the total amount of chloride taken up over a 120-sec incubation period. Specific GABA-dependent 36Cl- uptake (the difference between total and background uptake) was essentially complete within 15 sec of incubation. 2. Incubation with GABA following preincubation with 10 microM endrin, a polychlorocycloalkane insecticide and established blocker of GABA-gated chloride channels, showed a stimulation of uptake over background levels that was much slower in onset than that observed with GABA alone but nevertheless achieved virtually the same level of stimulation above background levels after 90 sec of incubation with GABA. 3. In electrophysiological assays of GABA receptors expressed in Xenopus oocytes following injection with rat brain mRNA, endrin (20 microM) effectively blocked the transient currents elicited by brief exposure of oocytes to GABA (200 microM). However, prolonged exposure to GABA in the absence of perfusion produced a large, slowly-developing inward current. 4. The actions of several known GABA antagonists were also compared as inhibitors of GABA-dependent 36Cl- uptake into mouse brain vesicles at short (4 sec) and long (120 sec) incubation times using concentrations of inhibitors known to produce approximately 70-90% inhibition of GABA-dependent chloride uptake in 4-sec incubations. Picrotoxinin and TBPS, like endrin, were completely ineffective as inhibitors in 120-sec incubations. In contrast, bicuculline was almost as effective at 120 sec as at 4 sec, and avermectin Bla produced approximately 50% inhibition of the GABA response after 120 sec.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Chloride Channels; Chlorides; Convulsants; Endrin; GABA Antagonists; gamma-Aminobutyric Acid; Ion Channel Gating; Kinetics; Male; Membrane Proteins; Mice; Mice, Inbred ICR; Picrotoxin; Rats; Rats, Inbred Strains; Receptors, GABA-A; Sesterterpenes; Xenopus

Ontogenesis of the convulsant (picrotoxinin or t-butylbicyclophosphorothionate (TBPS] site(s) was defined in chicken embryonic brain with the radioligands [35S]TBPS and [3H]t-butylbicycloorthobenzoate [( 3H]TBOB). Binding of the radioligands is detectable from day 6 of incubation. The increase in binding after day 14 of incubation is due to an increase in the number of binding sites. The pharmacological properties of the embryonic recognition site(s) do not undergo significant changes during hatching based on the affinity of embryonic and chick brain membranes for [3H]TBOB; the rate of association and dissociation for TBOB; non-competitive inhibition of [3H]TBOB binding and modulation of 1R, alpha S-cis-cypermethrin interaction with the recognition site(s) by GABA; and inhibition of radioligand binding by endrin, picrotoxinin and TBPS. Early development and in vitro susceptibility of the recognition site to convulsive toxicants makes the embryo a possible target for a variety of drugs and environmental toxicants acting at this site.

Topics: Aging; Animals; Brain Chemistry; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Chick Embryo; Convulsants; Endrin; Kinetics; Membranes; Picrotoxin; Receptors, GABA-A; Sesterterpenes

Three major classes of chlorinated hydrocarbon insecticides, i.e., the lindane/hexachlorocyclohexane, toxaphene and aldrin/dieldrin types, are potent, competitive, and stereospecific inhibitors of t-butylbicyclophosphorothionate (TBPS) binding to brain-specific sites, thereby indicating an action at the gamma-aminobutyric acid (GABA)-regulated chloride channel. The most inhibitory and toxic of four isomers of hexachlorocyclohexane is lindane and of greater than 188 components of toxaphene is 2,2,5-endo, 6-exo,8,9,9,10-octachlorobornane. 12-Ketoendrin (IC50 = 36 nM) is twice as active as the most potent previously known inhibitor of TBPS binding and it is also the most inhibitory and toxic of 22 cyclodienes examined. Within each of these three series of polychlorocycloalkanes the mammalian toxicity is closely related to the potency for inhibition of TBPS binding. A modified receptor assay incorporating liver microsomes and reduced nicotinamide-adenine dinucleotide phosphate compensates in part for oxidative detoxification and bioactivation. Specific TBPS binding is reduced in a dose-dependent manner in dieldrin-poisoned rats. DDT, mirex and kepone are not inhibitors of TBPS binding, even at 10 microM.

Topics: Animals; Binding, Competitive; Brain; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cycloparaffins; Endrin; Hexachlorocyclohexane; Insecticides; Isomerism; Kinetics; Microsomes; NADP; Picrotoxin; Rats; Receptors, Cell Surface; Receptors, GABA-A; Sesterterpenes; Synaptic Membranes; Toxaphene