Translocator Protein (18 kD) as Target for Anxiolytics Without Benzodiazepine-Like Side Effects

Abstract

Most antianxiety drugs (anxiolytics) work by modulating neurotransmitters in the brain. Benzodiazepines are fast and effective anxiolytic drugs; however, their long-term use is limited by the development of tolerance and withdrawal symptoms. Ligands of the translocator protein [18 kilodaltons (kD)] may promote the synthesis of endogenous neurosteroids, which also exert anxiolytic effects in animal models. Here, we found that the translocator protein (18 kD) ligand XBD173 enhanced gamma-aminobutyric acid-mediated neurotransmission and counteracted induced panic attacks in rodents in the absence of sedation and tolerance development. XBD173 also exerted antipanic activity in humans and, in contrast to benzodiazepines, did not cause sedation or withdrawal symptoms. Thus, translocator protein (18 kD) ligands are promising candidates for fast-acting anxiolytic drugs with less severe side effects than benzodiazepines.

Determination of [11C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

“…The polymorphism plot 10 enables the estimation of V ND by modeling the difference in the HAB and MAB signals across regions of differing target density and is derived from similar principles concerning occupancy studies. 16 This method assumes that the target density is the same for subjects within each genetic group, that the relative regional density is preserved across genetic groups, and V ND is the same for all subjects. These assumptions lead to the following equation, …”

Acute Shift in Glutamate Concentrations Following Experimentally Induced Panic with Cholecystokinin Tetrapeptide—A 3T-MRS Study in Healthy Subjects

“…Similarly, anxiolytics such as the benzodiazepine alprazolam ameliorate CCK-4-induced panic attacks in healthy volunteers (Zwanzger et al, 2003). Such effects have also been observed in larger samples using XBD173, a ligand of the translocator (TPSO) protein (Rupprecht et al, 2009), which recently has been identified as a possible new treatment target for anxiety (Rupprecht et al, 2010;Nothdurfter et al, 2012). As shown by neuroimaging studies, experimentally induced panic attacks are accompanied by a significant activation of neuroanatomical key areas responsible for the processing of fear and anxiety, such as the amygdala, hippocampus, insula, and the anterior cingulate cortex (ACC) (Schunck et al, 2006;Eser et al, 2009).…”

Structural Integrity of the A147T Polymorph of Mammalian TSPO

“…Expression of TSPO is upregulated in conditions of neuroinflammation as found in Alzheimer's and Parkinson's disease [5]. TSPO is a secondary binding site for benzodiazepines [6], and small molecules targeting TSPO might become useful in treating anxiety [7]. At the carboxylic terminus, TSPO contains a cholesterol recognition amino acid consensus (CRAC) sequence [8].…”