Antagonism of ethanol effects on cerebellar Purkinje neurons by the benzodiazepine inverse agonists Ro 15-4513 and FG 7142: electrophysiological studies.
Ro 15-4513, a benzodiazepine inverse agonist, has been reported to antagonize the ataxic effects of ethanol. The present study investigates the Ro 15-4513 sensitivity of rat cerebellar Purkinje neurons to the depressant effects of locally applied ethanol. Local applications of ethanol by pressure ejection from multibarrel micropipettes caused reversible and dose-dependent depressions of the neuronal firing rates of single cerebellar Purkinje neurons. The ethanol-induced depressions could be antagonized by local applications of Ro 15-4513 applied from another barrel of the same micropipette. This antagonism was not competitive, suggesting that Ro 15-4513 does not interfere directly with the initial step of the ethanol mechanism of action. A beta-carboline inverse agonist, FG 7142, was more efficacious than Ro 15-4513 for antagonizing the ethanol-induced depressions, but appeared to be less potent. Recovery of ethanol-induced depressions of Purkinje neurons firing rates after Ro 15-4513 antagonism was not usually observed for 1 hr or more after the antagonist application. In contrast to ethanol effects, qualitatively similar gamma-aminobutyric acid-induced depressions of these same neurons were not antagonized by the doses of Ro 15-4513 used. We conclude that the electrophysiological depressant effects of ethanol on cerebellar neuronal activity can be antagonized by the benzodiazepine inverse agonists, Ro 15-4513 and FG 7142.
Palmer
M R
MR
Department of Pharmacology, University of Colorado Health Sciences Center, Denver.
van Horne
C G
CG
Harlan
J T
JT
Moore
E A
EA
D000818:Animals; D001386:Azides / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology*; D018118:Chloride Channels; D002712:Chlorides; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000037:antagonists & inhibitors*; D006329:Heart Conduction System / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D001386:Azides; D002243:Carbolines; D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; C035874:FG 7142; C042957:Ro 15-4513