Benzodiazepine/barbiturate/GABA receptor-chloride ionophore complex in a genetic model for generalized epilepsy.
The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) acts through postsynaptic receptor sites which regulate membrane chloride ion channels. The GABA receptor-ionophore complex also contains modulatory receptor sites for two classes of centrally acting drugs, one for the benzodiazepines, and a second for both barbiturates and related depressants and for picrotoxin and related convulsants. The presence of these drug modulatory sites, directly on the GABA receptor protein, is consistent with other experimental observations; blocking GABA function can cause seizures, and augmenting GABA function can afford protection against seizures. This, and other circumstantial evidence, has suggested the possibility that a functional GABA deficit may be involved in some kinds of human epilepsy. Some neurochemical markers for GABA synapses have been reported to be altered in certain animal models as well as in human temporal lobe epilepsy. We have examined the postsynaptic GABA receptor complex using receptor binding assays for GABA, benzodiazepine (BZ), and barbiturate receptor sites in the seizure-susceptible gerbil, a genetic model of generalized epilepsy. A 30% deficit in BZ receptor binding was observed in the midbrain of seizure-sensitive animals relative to normal controls. This was shown by quantitative brain-slice binding autoradiography to involve a decrease in the number of binding sites in the substantia nigra (SN) and periaqueductal gray regions. A deficit in membrane receptors for BZs (which are linked to a subtype of postsynaptic GABA receptors) in a crucial region of brain might therefore contribute to seizure susceptibility in some kinds of epilepsy.
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D001463:Barbiturates / Q000378:metabolism; D001569:Benzodiazepines / Q000378:metabolism; D001665:Binding Sites; D002712:Chlorides / Q000378:metabolism*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000662:veterinary*; D005849:Gerbillinae; D007476:Ionophores / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism* / Q000502:physiology; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D012376:Rodent Diseases / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000209:etiology; D005680:gamma-Aminobutyric Acid / Q000172:deficiency
D000927:Anticonvulsants; D001463:Barbiturates; D002712:Chlorides; D007476:Ionophores; D011963:Receptors, GABA-A; D017981:Receptors, Neurotransmitter; C030975:barbiturate receptor; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid