Profound stress-induced alterations in flurazepam's antiseizure efficacy can be attenuated

Abstract

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 Ro 15–1788, 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 Ro 15–1788 may have a novel indication as a prophylactic intervention for individuals at risk for exposure to severe and unusual stress.