Étifoxine,neurostéroïdes et anxiété

Anxiety states are related to the hypofunctioning of GABAergic inhibitory synaptic transmission in certain regions of the encephalon. Benzodiazepines are currently used in the treatment of anxiety states, but they are associated with side effects (sedation, amnesia) and their use in long-term treatment poses problems of functional tolerance. Benzodiazepines bind to specific sites located on the GABA_A receptor channels that underlie rapid GABAergic transmission and potentiate their functioning. Neurosteroids such as allopregnanolone that are reduced in positions 3α and 5α (3α5α-NS) also potentiate GABA_A receptor function and may be considered as endogenous anxiolytics. Neurosteroids are distinguished from other steroids by the fact that they are synthesised de novo in the nervous system by neurons and glial cells independently of circulating steroids. This synthesis occurs from cholesterol imported into the mitochondrion by a multiprotein complex of which the « peripheral benzodiazepine receptor », recently renamed TSPO (translocator protein of 18 kDa), forms a part. The majority of benzodiazepines bind to this protein and stimulate the transfer of cholesterol and consequently neurosteroidogenesis. These effects can be blocked pharmacologically by PK11195, which acts as an antagonist at the mitochondrial binding site for benzodiazepines. Cholesterol is transformed in the mitochondrion to pregnenolone, the universal precursor of all steroids. Pregnenolone then leaves the mitochondrion and the nature of the steroids synthesised in the cytoplasm will depend on the type of neurosteroidogenesis enzymes expressed by the cell.Etifoxine does not possess a benzodiazepine-related structure but does exhibit anxiolytic effects. The objective of our study consequently was to understand the mechanism of action of this compound by studying its effects on the functional properties of GABA_A receptors and on GABAergic synaptic transmission. Binding tests on isolated membranes have revealed that etifoxine binds directly to the GABA_A receptor and the peripheral benzodiazepine receptor (TSPO). Electrophysiological experiments have shown that etifoxine dose-dependently potentiates membrane currents induced by the application of submaximal but not of saturating concentrations of GABA. Etifoxine also facilitates GABAergic transmission in hypothalamic neuronal cultures and increases the amplitude of a sustained GABAergic current due to the tonic activation of GABA_A receptors by a weak GABA concentration in the extracellular space. The effect of etifoxine on this current is partially antagonised by PK11195 but not by flumazenil, an antagonist of the benzodiazepine binding sites on the GABA_A receptor.All of our data indicate that etifoxine facilitates GABAergic inhibition by two types of action: 1] by directly potentiating the activity of GABA_A receptors via an allosteric modulatory different site from that of the benzodiazepines, and 2] by stimulating the production of 3α5α-NS, which in turn potentiate the activity of GABA_A receptors. These two effects are independent and additive. They therefore contribute to make GABAergic transmission more effective.