Profound stress-induced alterations in flurazepam's antiseizure efficacy can be attenuated.
A new procedure is described for assessing the sensitivity of the benzodiazepine receptor in intact animals. This procedure measures the ability of benzodiazepines to antagonize electrically-induced seizures precipitated by incremental increases in voltage. This functional measure detected stress-induced alterations in benzodiazepine receptor sensitivity, an alteration shown previously with in vitro and in vivo receptor binding techniques. In contrast, mouse rotorod performance, which has been proposed as a behavioral measure of benzodiazepine receptor sensitivity did not show stress-induced alterations. The mechanism of these stress-induced alterations was explored using this incremental electroconvulsive shock procedure (IECS). A 'GABA-negative' benzodiazepine mimicked the effects of swim stress, whereas treatment of animals prior to swim stress with Ro15-1788, a 'GABA-neutral' benzodiazepine, attenuated these stress-induced alterations. These data suggest both that these stress effects may be mediated by an endogenous ligand, and that Ro15-1788 may have a novel indication as a prophylactic intervention for individuals at risk for exposure to severe and unusual stress.
Psychiatry Service, Veterans Administration Medical Center, Washington, DC 20422.
S I
SI
Deutsch
R B
RB
Rosse
J A
JA
Huntzinger
M R
MR
Novitzki
J
J
Mastropaolo
D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D002998:Clonazepam / Q000494:pharmacology; D003080:Cold Temperature; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D005442:Flumazenil / Q000494:pharmacology; D005479:Flurazepam / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008874:Midazolam / Q000494:pharmacology; D012640:Seizures / Q000503:physiopathology*; D013315:Stress, Psychological / Q000503:physiopathology*
D002243:Carbolines; D005442:Flumazenil; D002998:Clonazepam; C035874:FG 7142; D005479:Flurazepam; D003975:Diazepam; D008874:Midazolam