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
GABA(A) 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
GABA(A) 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
GABA(A) receptor enhancer. The TSPO
ligand XBD173 enhances GABAergic neurotransmission via the promotion of neurosteroidogenesis without direct effects at the
GABA(A) 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.