Translocator Protein (18 kDa) as a Target for Novel Anxiolytics with a Favourable Side-Effect Profile

Anxiety disorders are frequent and highly disabling diseases with considerable socio-economic impact. In the treatment of anxiety disorders, benzodiazepines (BZDs) as direct modulators of the GABAA receptor are used as emergency medication because of their rapid onset of action. However, BZDs act also as sedatives and rather quickly induce tolerance and abuse liability associated with withdrawal symptoms. Antidepressants with anxiolytic properties are also applied as first line long-term treatment of anxiety disorders. However, the onset of action of antidepressants takes several weeks. Obviously, novel pharmacological approaches are needed that combine a rapid anxiolytic efficacy with the lack of tolerance induction, abuse liability and withdrawal symptoms. Neurosteroids are potent allosteric modulators of GABAA receptor function. The translocator protein (18 kDa) (TSPO) plays an important role for the synthesis of neurosteroids by promoting the transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Etifoxine not only exerts anxiolytic effects as a TSPO ligand by enhancing neurosteroidogenesis, but also acts as a weak direct GABAA receptor enhancer. The TSPO ligand XBD173 enhances GABAergic neurotransmission via the promotion of neurosteroidogenesis without direct effects at the GABAA receptor. XBD173 counteracts pharmacologically-induced panic in rodents in the absence of sedation and tolerance development. Also in humans, XBD173 displays antipanic activity and does not cause sedation and withdrawal symptoms after 7 days of treatment. XBD173 therefore appears to be a promising candidate for fast-acting anxiolytic drugs with less severe side-effects than BZDs. In this review, we focus on the pathophysiology of anxiety disorders and TSPO ligands as a novel pharmacological approach in the treatment of these disorders.