Benzodiazepine/gamma-aminobutyric acid receptor deficit in the midbrain of the seizure-susceptible gerbil.
The density of benzodiazepine/gamma-aminobutyric acid receptor binding sites was lower in the midbrain of seizure-susceptible gerbils compared to control seizure-resistant gerbils. Binding of [3H]diazepam to high-affinity brain-specific sites in membrane homogenates of gerbil brain showed a 20-30% lower binding in midbrain (but not other regions) in adult seizure-susceptible gerbils than in controls. This binding deficit was localized by tissue slice autoradiography with [3H]flunitrazepam to the substantia nigra and mesencephalic periaqueductal gray regions, while higher binding was observed in the interpeduncular nucleus. These differences were also seen in animals sacrificed immediately after a seizure. A parallel deficit of [3H]bicuculline methochloride binding to low-affinity gamma-aminobutyric acid receptors also was seen in the same midbrain regions. Scatchard plot analysis showed that the benzodiazepine binding deficit in the nigra was due to a lower number of binding sites with not significant difference in affinity. Lower [3H]flunitrazepam binding was likewise seen in younger animals (29% lower at 30 days of age, 38% at 60 days, and 21% at 90 days), indicating that the midbrain receptor deficit is present in the seizure-susceptible gerbil prior to the age of onset of seizures at 50-100 days. Therefore, these changes are not likely to result from seizures but reflect genetically determined biochemical differences that could play a role in the expression of seizure susceptibility. The deficit in midbrain benzodiazepine/gamma-aminobutyric acid receptors in the seizure-susceptible gerbil would be consistent with the hypothesis that a deficit of gamma-aminobutyric acid-mediated inhibition might contribute to some kinds of epilepsy.
D000818:Animals; D001640:Bicuculline / Q000031:analogs & derivatives / Q000378:metabolism; D003975:Diazepam / Q000378:metabolism; D004195:Disease Models, Animal / Q000235:genetics / Q000378:metabolism*; D005445:Flunitrazepam / Q000378:metabolism; D005849:Gerbillinae / Q000378:metabolism*; D008636:Mesencephalon / Q000032:analysis*; D009118:Muscimol / Q000378:metabolism; D010424:Pentobarbital / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000172:deficiency* / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000235:genetics / Q000378:metabolism*
D011963:Receptors, GABA-A; D009118:Muscimol; D005445:Flunitrazepam; C006749:bicuculline methochloride; D010424:Pentobarbital; D003975:Diazepam; D001640:Bicuculline