[The benzodiazepine receptor: the enigma of the endogenous ligand]

The structure of the benzodiazepine receptor is nowadays well established and its potentialisation of GABA neurotransmission is known as the main action mechanism of benzodiazepinic drugs. Three categories of ligands have been also identified with radically different effects: the agonists (like diazepam and other anxiolytics), the antagonists (like flumazenil) and the inverse agonists which are anxiogenic, pro-convulsant and alerting (like beta-carbolines). By analogy with opiates system, the existence of a possible endogenous ligand has been proposed, and if such a substance really exists, it could be an important biological support of anxiety regulation. Many compounds with benzodiazepine receptor affinity have been extracted from the brain, the cerebrospinal fluid and the urine of animals but also of humans. Among these, some are artefacts, like ethyl-beta-carbolin, or their affinity are to low to be physiologically relevant. N-desmethyl-diazepam has been purified from the brain of never treated humans, but probably comes from diet or gut bacteria. An important candidate is the DBI (Diazepam Binding Inhibitor), which displays inverse agonist activity and is present in human organism. Its role as a modulator of GABAergic transmission is questioned. Likewise, the intervention of endogenous agonist compounds is possible during acquisition tasks with stress or anxiety in animals. There are also reasonable arguments to involve an agonist (sedative) ligand in the pathogenesis of hepatic encephalopathy. On the other hand, inverse agonists are not implicated in benzodiazepine withdrawal and panic disorder mechanisms. Lastly, probably indirect interactions between benzodiazepine receptor and cholecystokinin system are important to be considered, with possible consequences on anxiety regulations.