Differential seizure sensitivities to picrotoxinin in two inbred strains of mice (DBA/2J and BALB/c ByJ): parallel changes in GABA receptor-mediated chloride flux and receptor binding.
Two strains of mice were shown to possess a differential sensitivity to picrotoxinin-induced convulsions; picrotoxinin elicited both tonic and clonic seizures at lower doses in the DBA/2J (DBA) strain compared to the BALB/c ByJ (BALB) strain. Less protection of picrotoxinin-induced tonic seizures was afforded by pentobarbital in the DBA strain. Biochemical studies revealed that picrotoxin inhibited 36Cl- efflux from forebrain synaptoneurosomes only in the DBA strain. In addition, picrotoxin inhibited pentobarbital-induced 36Cl- efflux to a greater extent in the DBA strain. No differences were observed in the binding of [3H]muscimol or [35S]t-butylbicyclophosphorothionate (TBPS) to forebrain homogenates, while pentobarbital was a less potent inhibitor of [35S]TBPS binding in the DBA strain. These findings suggest a genetic basis for the behavioral differences in convulsant sensitivity as well as for the neurochemical differences in allosteric coupling between convulsant and depressant/anticonvulsant sites associated with the GABA receptor-gated Cl- channel.
Schwartz
R D
RD
Clinical Neuroscience Branch, NIMH, Bethesda, MD 20892.
Seale
T W
TW
Skolnick
P
P
Paul
S M
SM
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005625:Frontal Lobe / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C / Q000502:physiology*; D008811:Mice, Inbred DBA / Q000502:physiology*; D009118:Muscimol / Q000378:metabolism; D010424:Pentobarbital / Q000494:pharmacology; D010852:Picrotoxin; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology; D013045:Species Specificity; D013574:Synaptosomes / Q000502:physiology
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D009118:Muscimol; D010424:Pentobarbital; D010852:Picrotoxin; D011963:Receptors, GABA-A; C037476:tert-butylbicyclophosphorothionate