Physical dependence induced in DBA/2J mice by benzodiazepine receptor full agonists, but not by the partial agonist Ro 16-6028.
Continuous administration of triazolam, alprazolam or diazepam for a 7-day period by means of minipumps or chronic (17 days) p.o. treatment with alprazolam induced clear physical dependence in DBA/2J mice as assessed by precipitation of a withdrawal syndrome with an i.v. injection of the benzodiazepine receptor partial inverse agonist Ro 15-3505. In contrast, no precipitated withdrawal signs were observed following chronic exposure to high doses of the benzodiazepine receptor partial agonist Ro 16-6028. The use of minipumps and precipitation with a benzodiazepine receptor antagonist permits a simple and rapid evaluation of the physical dependence liability of potent compounds acting at the benzodiazepine receptor. Furthermore, these results support the hypothesis that benzodiazepine receptor partial agonists are less likely to induce physical dependence than full agonists.
Moreau
J L
JL
Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Jenck
F
F
Pieri
L
L
Schoch
P
P
Martin
J R
JR
Haefely
W E
WE
D000284:Administration, Oral; D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D004343:Drug Implants; D051379:Mice; D008811:Mice, Inbred DBA; D011963:Receptors, GABA-A / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D019966:Substance-Related Disorders; D014229:Triazolam / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D004343:Drug Implants; D011963:Receptors, GABA-A; D014229:Triazolam; C040725:Ro 15-3505; C054626:bretazenil; D003975:Diazepam; D000525:Alprazolam