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Science 325 (5939): 490-493

Copyright © 2009 by the American Association for the Advancement of Science

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

Rainer Rupprecht,1,2,* Gerhard Rammes,2,3 Daniela Eser,1 Thomas C. Baghai,1 Cornelius Schüle,1 Caroline Nothdurfter,1,2 Thomas Troxler,4 Conrad Gentsch,4 Hans O. Kalkman,4 Frederique Chaperon,4 Veska Uzunov,4 Kevin H. McAllister,4 Valerie Bertaina-Anglade,5 Christophe Drieu La Rochelle,5 Dietrich Tuerck,6 Annette Floesser,4 Beate Kiese,7 Michael Schumacher,8 Rainer Landgraf,2 Florian Holsboer,2 Klaus Kucher4

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.

1 Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Nussbaumstrasse 7, Munich 80336, Germany.
2 Max-Planck-Institute of Psychiatry, Kraepelinstrasse 2, Munich 80804, Germany.
3 Department of Anaesthesiology, Technische Universität, Munich 81675, Germany.
4 Novartis Institute for Biomedical Research (NIBR), Neuroscience, 4056 Basel, Switzerland.
5 Biotrial, 3500 Rennes, France.
6 Drug Metabolism and Pharmacokinetics, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland.
7 Biostatistics, Novartis Pharma AG, 4056 Basel, Switzerland.
8 INSERM UMR 788, and University Paris-Sud 11, 94274 Paris, France.

* To whom correspondence should be addressed. E-mail: rainer.rupprecht{at}med.uni-muenchen.de

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