Flumazenil induces benzodiazepine partial agonist-like effects in BALB/c but not C57BL/6 mice

Abstract

Flumazenil induces partial agonist-like effects in BALB/c and not in C57BL/6 mice, suggesting a possible benzodiazepine receptor set point shift toward the agonistic direction in some pathological anxiety states such as generalised anxiety disorder.

The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic

“…The effects of flumazenil on flight may well fit with clinical observations that the drug is somewhat anxiogenic in healthy volunteers (Darragh et al, 1983;Duka et al, 1986;Schopf et al, 1984) and that it increases the frequency of panic attacks in panic disorder patients (Maddock, 1998;Nutt et al, 1990;Woods et al, 1991). The weak agonist-like activity of flumazenil on defensive aggression is at first glance surprising, but it may fit with the idea that the drug can produce a GABA A -benzodiazepine receptor set point shift either toward the agonistic or the inverse agonistic direction, depending on the aversiveness of the situation (Belzung et al, 2000).…”

Measuring normal and pathological anxiety-like behaviour in mice: a review

“…Finally, this strain also exhibits some particular features in the sensitivity to anxiolytic agents. Indeed, it has a high sensitivity to the anxiolytic action of BZs [34] and low doses of the BZ receptor antagonist flumazenil induce an anxiolytic-like action in this strain [9]. Furthermore, naloxone, an opioid antagonist, blocks the anxiolytic-like action of BZs in SWISS and C57Bl/6 mice, but not in BALB/c mice, an effect probably related to abnormality in k-opioidergic receptors [1,5,8].…”

Behavioral effects of flumazenil in the social conflict test in mice

“…Although we cannot exclude that lower doses of flumazenil might be anxiogenic in the present experimental model, this seems unlikely because markedly lower doses of flumazenil (0.0001-1 mg/kg) still pro- duced anxiolytic effects in the elevated plus maze test in mice (Belzung et al 2000). There appeared to be some tendency to increased timidity in sociable mice, but this was significant only at the medium dose (20 mg/kg) and in one parameter (the latency to timid acts).…”

“…behavioral, genetic, biochemical) have been studied rarely so far. Flumazenil produced anxiolytic effects in the elevated plus maze and the light/ dark test in BALB/c mice but not in C57BL/6 mice (Belzung et al 2000). Significant differences in brain levels of DBI and other peptides regulating anxiety were found in two inbred rat strains exhibiting different levels of anxiety (Sudakov et al 2001).…”

“…Although this could be explained by differences in experimental models, there are many examples of contradictory results of flumazenil effects on anxiety obtained with the same method. For example, disparate effects of flumazenil were found in the elevated plus-maze test in mice: flumazenil increased the time spent on the closed arms of the maze (an anxiogenic profile; Lee and Rodgers 1991), produced no effect (Dalvi and Rodgers 1999) and induced strong anxiolytic effect (Belzung et al 2000). The inconsistencies in flumazenil effects on anxiety represent a problem in the investigation of putative endogenous ligands of BZRs.…”