Elsevier

Medical Hypotheses

Volume 81, Issue 6, December 2013, Pages 1075-1077
Medical Hypotheses

Endogenous ligands of benzodiazepine binding site have inverse agonistic properties

https://doi.org/10.1016/j.mehy.2013.10.006Get rights and content

Abstract

Benzodiazepines have been widely used in clinical praxis for many decades. They act as GABAA receptor agonists and possess muscle-relaxant, hypnotic-sedative, anticonvulsant, and anxiolytic properties. Flumazenil acts as a benzodiazepine receptor antagonist (subunits α1, α2, α3, and α5) or partial agonist (subunits α4 and α6). It competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepines. In our experiments, administration of flumazenil in rabbits was surprisingly associated with anxiolytic effects similar to those of midazolam. Additionally, flumazenil significantly and dose-dependently decreased the total number of vocalizations in rats, i.e. it was anxiolytic. These observations seem to be in contrast to the effect of flumazenil in humans, where it is believed to produce mainly anxiogenic effects. It seems that in individuals, who exhibit anxiogenic behavior or in individuals with anticipation anxiety, flumazenil acts as an anxiolytic agent, while in individuals without any signs of anxiety, flumazenil can also act as anxiogenic agent. Thus, we hypothesize that flumazenil is associated with decreased intensity of anticipatory anxiety due to occupancy of benzodiazepine binding sites by an endogenous ligand with inverse agonistic properties.

Introduction

Benzodiazepines (BZDs) are widely used around the world, mainly, but not limited, for their anxiolytic and hypnotic properties. BZDs act selectively on GABAA receptors, which mediate inhibitory synaptic transmission throughout the central nervous system. They bind specifically to a regulatory site on these receptors and act allosterically to increase the affinity of GABA for the receptor. Thus, they enhance the response to GABA by facilitating the opening of GABA-activated chloride channels. Although the BZD binding site is relatively well described, no endogenous ligand has been discovered so far and we can only indirectly predict its potential activity.

Flumazenil acts as a benzodiazepine receptor antagonist (subunits α1, α2, α3, and α5) or partial agonist (subunits α4 and α6). Therefore it competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepines. The main clinical indication of flumazenil is the management of benzodiazepine overdose and/or to reverse the effects of benzodiazepines after general anesthesia; one potential adverse drug reaction is an anxiogenic effect.

However, some studies have suggested that flumazenil itself also causes sedation and to some extent even produces anxiolytic effects, especially in anticipation anxiety [1]. Surprisingly, there is very little evidence regarding direct flumazenil effects on behavior, despite several interesting findings in the scientific literature showing anxiolytic effects of this antagonist. Chronic administration of flumazenil in rats has been associated with significantly longer times in open arms and with fewer fecal boluses in plus-maze tests compared to placebo. Additionally, flumazenil treated animals showed increased exploratory activity during the hole-board test and no change in drinking following a ‘shock experience’ in the drinking-punishment test [2]. Anxiolytic activity of flumazenil has also been observed in humans, where a double-blind study showed significantly reduced anxiety induced by simulation of public speaking [3].

In this paper we hypothesize that this “paradoxical” effect of flumazenil on behavior is caused by characteristics of endogenous ligands of BZD binding sites.

Section snippets

Hypothesis

Based on available knowledge [4], [3], [5] and our preliminary results [6], we predict that the putative endogenous ligand of the BZD binding site on GABAA receptors has inverse agonistic properties. On the one hand, agonists of BZD binding sites are antagonized by flumazenil; while on the other hand, flumazenil is able to antagonize symptoms caused by benzodiazepine withdrawal [1], [7], [8], [9]. It has been suggested that flumazenil “resets” GABAA receptors for normal function [10].

There is a

Data in support of and against hypothesis

In our preliminary experiments with flumazenil, we observed that administration of flumazenil (0.1 mg/kg), to rabbits, was associated with sedative and anxiolytic effects, which was, in some parameters, similar to that of midazolam (0.5 mg/kg). In treated rabbits, the loss of the righting reflex was achieved after approximately 3 min, irrespective of drug (midazolam or flumazenil). On the other hand, midazolam caused a more profound decrease in blood pressure and pulse rate. Such results were

Consequences of the hypothesis and discussion

Our hypothesis might also elucidate some effects of flumazenil in clinical practice. It explains administration of flumazenil is associated with decreased intensity of anticipatory anxiety and why flumazenil can antagonize some symptoms caused by BZD withdrawal. A substance with antagonistic properties, such as flumazenil, can decrease the level of anxiety due to occupancy of BZD binding sites by an endogenous ligand with inverse agonistic properties. This hypothesis is supported by laboratory

Conflict of interest

Authors declare no conflict of interests.

Acknowledgement

This work was supported by grant IGA MZ NS/10503-3 from the Czech Ministry of Health.

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