Benzodiazepine/γ -aminobutyric Acid Receptor Deficit in the Midbrain of the Seizure-Susceptible Gerbil

• Published in: Proceedings of the National Academy of Sciences - PNAS 1985-10, Vol.82 (19), p.6701-6705
• Main Authors: Olsen, Richard W., Wamsley, James K., McCabe, R. Tyler, Lee, Randall J., Lomax, Peter
• Format: Article
• Language: English
• Subjects: Animals; Applied sciences; Autoradiography; Benzodiazepines; Bicuculline - analogs & derivatives; Bicuculline - metabolism; Biological and medical sciences; Diazepam - metabolism; Disease Models, Animal - genetics; Disease Models, Animal - metabolism; Exact sciences and technology; Flunitrazepam - metabolism; GABA receptors; Gerbillinae - metabolism; Hippocampus; Ligands; Medical sciences; Mesencephalon - analysis; Midbrain; Muscimol - metabolism; Nervous system involvement in other diseases. Miscellaneous; Neurology; Other techniques and industries; Pentobarbital - pharmacology; Periaqueductal gray; Receptors; Receptors, GABA-A - deficiency; Receptors, GABA-A - drug effects; Receptors, GABA-A - metabolism; Seizures; Seizures - genetics; Seizures - metabolism; Substantia nigra
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.82.19.6701

The density of benzodiazepine/γ -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 brainspecific 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 γ -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 no 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/γ -aminobutyric acid receptors in the seizure-susceptible gerbil would be consistent with the hypothesis that a deficit of γ -aminobutyric acid-mediated inhibition might contribute to some kinds of epilepsy.