Functional properties of GABAA receptors in two rat lines selected for high and low alcohol sensitivity.
The effects of lorazepam and sodium barbital on GABAA receptor function were evaluated in rat lines selected for differential sensitivity to the motor-impairing effects of ethanol [alcohol-insensitive (AT) and alcohol-sensitive (ANT) lines]. The effect of GABA on [3H]flunitrazepam and [3H]Ro 15-4513 binding and the effects of lorazepam and sodium barbital on [3H]muscimol binding were measured in cerebellar, cerebrocortical, and hippocampal membrane preparations. The effects of lorazepam and sodium barbital on muscimol-stimulated 36Cl- influx were measured using membrane vesicle suspensions from the same brain areas. No differences were found between the rat lines in the GABA-induced stimulation of [3H]flunitrazepam binding or in the lorazepam and sodium barbital-induced enhancement of either [3]muscimol binding or muscimol-stimulated 36Cl- flux. Neither was desensitization of the 36Cl- flux affected differently by ethanol, lorazepam, and barbital in vitro between the lines. The affinity of cerebellar diazepam-insensitive (DZ-IS) [3H]Ro 15-4513-binding sites for benzodiazepine agonists has been shown to be much greater in the ANT than the AT rats. In the present study, at 0 degrees C, GABA decreased [3H]Ro 15-4513 binding in the presence of diazepam only in ANT rats. Similarly, GABA decreased this binding at 37 degrees C in ANT rats having a high affinity for diazepam, whereas it enhanced the binding in all AT samples in those ANT samples where diazepam had a poor AT-like affinity. The decrease in binding in ANT samples is apparently caused by the enhancing effect of GABA on diazepam binding to DZ-IS [3H]Ro 15-4513-binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
Uusi-Oukari
M
M
Department of Biomedical Sciences, University of Tampere, Finland.
Korpi
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D000818:Animals; D001386:Azides / Q000378:metabolism; D001462:Barbital / Q000494:pharmacology; D001569:Benzodiazepines / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D004351:Drug Resistance; D000431:Ethanol / Q000494:pharmacology*; D005445:Flunitrazepam / Q000378:metabolism; D008140:Lorazepam / Q000494:pharmacology; D009118:Muscimol / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*; D013696:Temperature; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D001386:Azides; D002712:Chlorides; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D009118:Muscimol; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D001462:Barbital; D005445:Flunitrazepam; C042957:Ro 15-4513; D008140:Lorazepam