CNS biochemical and pharmacological effects of the isomers of hexachlorocyclohexane (lindane) in the mouse.
gamma-Hexachlorocyclohexane (gamma-HCH), the active ingredient of the insecticide lindane, has been shown to be a seizure-inducing agent in mammals. gamma-HCH and two non-convulsant isomers of HCH (alpha and delta) were compared as to their CNS-related pharmacological and biochemical effects. gamma-HCH was a potent seizure-inducing agent in mice while the alpha or the delta isomer significantly decreased mouse motor activity. Acute administration of gamma-HCH increased the severity of seizure activity of either pentylenetetrazol (PTZ) or picrotoxin (PIC). However, acute exposure to alpha- or delta-HCH inhibited the seizure activity due to PTZ but increased that of PIC. gamma-, alpha-, and delta-HCH inhibited the binding of 3H-TBOB (a ligand for the GABA-A receptor linked chloride channel) to mouse whole brain membranes with IC50 values of 4.6, 20.0, and 31.8 microM, respectively. All three isomers were weak inhibitors of GABA-stimulated uptake of 36Cl into mouse brain neurosynaptosome preparations in vitro, being much less potent than PIC, an agent known to act at the chloride channel. At concentrations producing no effect by itself, gamma-HCH increased the effect of PIC on GABA-stimulated chloride uptake. In combination with PTZ, the delta and alpha isomers decreased the effect of PTZ in vitro while the gamma isomer increased the effects of PTZ. These effects correspond to observations made on seizure activity. The results show that the non-seizure-inducing isomers of HCH have biochemical and pharmacological effects in the CNS which differ from those of the insecticidally relevant gamma isomer. The actions of the HCH isomers in the CNS appear to be mediated, at least in part, through GABA-A receptor linked chloride channel sites.
D000818:Animals; D001921:Brain / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides / Q000378:metabolism; D004357:Drug Synergism; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000633:toxicity; D010852:Picrotoxin / Q000633:toxicity; D011963:Receptors, GABA-A / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D001556:Hexachlorocyclohexane; D007473:Ion Channels; D010433:Pentylenetetrazole; D010852:Picrotoxin; D011963:Receptors, GABA-A; C046308:tert-butylbicyclo-2-benzoate