PT  - JOURNAL ARTICLE
AU  - H L June
AU  - S E Duemler
AU  - T L Greene
AU  - J A Williams
AU  - M Lin
AU  - S L Devaraju
AU  - S H Chen
AU  - M J Lewis
AU  - J M Murphy
TI  - Effects of the benzodiazepine inverse agonist RO19-4603 on the maintenance of tolerance to a single dose of ethanol.
DP  - 1995 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1105--1112
VI  - 274
IP  - 3
4099  - http://jpet.aspetjournals.org/content/274/3/1105.short
4100  - http://jpet.aspetjournals.org/content/274/3/1105.full
SO  - J Pharmacol Exp Ther1995 Sep 01; 274
AB  - 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.