Effects of the benzodiazepine inverse agonist RO19-4603 on the maintenance of tolerance to a single dose of ethanol.
The time course of the novel benzodiazepine inverse agonist, RO19--4603 (0.075 or 0.150 mg/kg) in antagonizing the depressant effects of ethanol (EtOH) (0.50, 1.0 and 1.5 g/kg) and the development of tolerance on locomotor behaviors (e.g., ambulatory count, total distance and stereotypy count) were investigated in Sprague-Dawley rats given EtOH injections spaced at 24-hr intervals. A single dose of RO19--4603 prevented the development of tolerance to the 0.50- and 1.0-g/kg EtOH doses 24-hr post-RO19--4603 administration on most locomotor behaviors. On Day 1, the 0.150-mg/kg RO19--4603 dose prevented the reduction of motor behaviors after the 1.0- and 1.5-g/kg EtOH doses, whereas the 0.075-mg/kg RO19--4603 dose prevented the reduction of motor behaviors only after the 1.5-g/kg EtOH dose. The 0.075- and 0.150-mg/kg RO19--4603 doses also prevented the EtOH-induced reduction of motor behaviors after the 1.5-g/kg EtOH dose 24-hr post-RO19--4603 administration. RO19--4603 was without effect on activity when given alone. These data suggest that the motor impairing effects of EtOH and the development of tolerance to them may involve gamma-aminobutyric acidA-benzodiazepine receptor mechanisms that when occupied, even briefly by certain benzodiazepine inverse agonists, produce long-lasting effects on locomotion and tolerance.
June
H L
HL
Department of Psychology, Purdue School of Science, Indiana University-Purdue University, Indianapolis, USA.
Duemler
S E
SE
Greene
T L
TL
Williams
J A
JA
Lin
M
M
Devaraju
S L
SL
Chen
S H
SH
Lewis
M J
MJ
Murphy
J M
JM
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000819:agonists*; D004361:Drug Tolerance; D000431:Ethanol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D001381:Azepines; D018757:GABA Modulators; D001569:Benzodiazepines; D000431:Ethanol; D005442:Flumazenil; C056530:Ro 19-4603