A theory of benzodiazepine dependence that can explain whether flumazenil will enhance or reverse the phenomena

Abstract

Repeated administration of benzodiazepines (BDZs) produces dependence in man and animals and this is reflected in the phenomena of tolerance and withdrawal responses. In BDZ-dependent animals the BDZ-receptor antagonist flumazenil (Ro 15-1788) reverses the increased anxiety and decreased seizure threshold seen when benzodiazepine treatment is withdrawn. In contrast are reports that flumaenil enhances BDZ-withdrawal responses. Indirect influences on the direction of flumazenil's effects on anxiety are the duration and dose of BDZ treatment, whether tolerance has developed to its anxiolytic effect and whether there is an anxiogenic response on drug withdrawal. However, we conclude that the crucial factor is the anxiety level of the animal: when this is high flumazenil becomes anxiolytic; when this is low flumazenil is anxiogenic. These bidirectional effects of flumazenil can be seen in drug-naive and BDZ-dependent animals. We propose a theory of benzodiazepine dependence that can account for anxiogenic responses on drug withdrawal and for flumazenil's bidirectional effects; central to this theory is the assumption that flumazenil normalises the benzodiazepine receptor, returning it to a baseline state. Thus it is whether an animal's score lies above or below this baseline that will determine the direction of flumazenil's effect. The clinical implications of this theory are discussed. We suggest that during the development of benzodiazepine dependence, two independent adaptive biochemical mechanisms are triggered: one underlying the development of tolerance to the anxiolytic responses, the other underlying the incidence of increased anxiety on drug withdrawal. It is only changes in the latter that are induced by the administration of flumazenil.

Struggling and Flumazenil Effects in the Swimming Test Are Related to the Level of Anxiety in Mice

“…Thus, the present results give support to the hypothesis that strug gling behavior in the swimming test (at least in mice and in the present experimental conditions) is positively relat ed to the animals' anxiety level. The present data also con firm that low doses of flumazenil display different effects depending on the basal level of anxiety, as previously reported in different behavioral tests [14,18,19], Thus, the effects of flumazenil in the first swimming trial were in agreement with those found by File and Hitchcott [14] in rats with differential anxiety levels (as measured in the plus-maze). Consequently, the present flumazenil action extends those findings to mice and to a different testing situation and again suggests that anxiety plays a role in the swimming test.…”

“…On the other hand, it has been reported that low doses of flumazenil (a benzodiazepine receptor antagonist) dis play divergent effects when administered to animals with differing basal anxiety levels (as measured in the elevated plus-maze test of anxiety [12][13][14]). Those bidirectional effects have been interpreted as possibly indicating the existence of differential balances of anxiolytic and anxiogenic endogenous ligands of benzodiazepine receptors (depending upon the animals' anxiety level [ 14.…”

Flumazenil blockade of anxiety following ethanol withdrawal in rats

“…Under certain conditions, ßumazenil has been shown to have anxiolytic e¤ects in the elevated plus maze task (File and Hitchcott 1990), active avoidance procedures (Escorihuela et al 1992;Criswell and Breese 1993;Moy et al 1993), social interaction tests (File et al 1992), punished responding (Britton et al 1988), and on the anxiety induced in humans before and during public speaking (Kapczinski et al 1994). However, other researchers have demonstrated a lack of such intrinsic e¤ects by ßumazenil across several di¤erent testing paradigms (Polc et al 1981;Bonetti et al 1982;Auta et al 1993).…”

“…The following experiments also examined the e¤ect of ßumazenil in animals showing enhanced levels of anxiety due to withdrawal from chronic ethanol consumption. Previous studies have shown that ßumazenil can reverse the anxiogenic e¤ects of withdrawal from chlordiazepoxide or diazepam on the elevated plus maze (Baldwin and File 1988;File and Hitchcott 1990) and withdrawal from ethanol in a social interaction test (File et al 1989(File et al , 1992 and in a shuttle-box avoidance task . The e¤ect of ßumazenil on the anxiogenic properties of CRF was also determined.…”

Behavioral effects of flumazenil in the social conflict test in mice

“…According to this ("anxietyrelated") hypothesis, "the crucial factor is the anxiety level of the animal: when this is high flumazenil becomes anxiolytic; when this is low flumazenil is anxiogenic" (File and Hitchcott 1990). Regrettably, it is difficult to compare anxiety levels of different experimental situations in different laboratories and few attempts have been made to test flumazenil effects under low and high anxiety levels in the same laboratory and measure of anxiety.…”