Adaptation of the GABAA-receptor complex in rat brain during chronic elevation of GABA by ethanolamine O-sulphate.
Slice preparations of rat cuneate nucleus were used for studies on the gamma-aminobutyric acid GABAA-receptor complex following chronic and acute pretreatment with GABA-alpha-ketoglutarate aminotransferase (GABA-T) inhibitors. The whole brain GABA concentration was significantly increased 2.9 fold and 2.6 fold following treatment with ethanolamine O-sulphate (EOS, orally) for 15-30 days and 56-64 days, respectively. One hour after a single injection of gamma-acetylenic GABA (GAG) i.p., there was a significant 2.1 fold increase in whole brain GABA. Superfusion of a slice with muscimol or the GABA uptake inhibitor nipecotic acid depolarized the afferent nerve fibres. These effects were potentiated by flurazepam (1 microM) and pentobarbitone (10 microM) and antagonized by picrotoxin (3 microM, 30 microM). Following 15-30 days of EOS-treatment, the depolarization response to muscimol was decreased and that to nipecotic acid increased. These changes were no longer significant by 56-64 days of pretreatment. The acute dose of GAG did not affect the depolarization response to muscimol but increased that to nipecotic acid. The potentiations of muscimol by flurazepam (1 microM) and pentobarbitone (10 microM) were enhanced following chronic EOS treatment (15-64 days). The enhancement of flurazepam was less after 56-64 days than after 15-30 days pretreatment whereas the enhancement of pentobarbitone was similar at both times. Acute GAG treatment had no effect. The potency of picrotoxin as an antagonist of muscimol was reduced following chronic EOS treatment; the enhancement was less after 56-64 days than after 15-30 days pretreatment. Acute GAG treatment caused only a very small reduction in picrotoxin potency. Possible adaptations in the GABAA-receptor complex and its modulation during chronic elevation of brain GABA are discussed.
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D004983:Ethanolamines / Q000494:pharmacology*; D005479:Flurazepam / Q000494:pharmacology; D009118:Muscimol / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology*
D000612:4-Aminobutyrate Transaminase; D004983:Ethanolamines; D005479:Flurazepam; D009118:Muscimol; D009557:Nipecotic Acids; D010424:Pentobarbital; D010852:Picrotoxin; D011188:Potassium; D011392:Proline; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C030278:nipecotic acid; C020619:ethanolamine O-sulfate; C010983:homoproline