Hindawi Publishing Corporation Advances in Pharmacological Sciences Volume 2012, Article ID 416864, 19 pages doi:10.1155/2012/416864 Review Article Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators? Christiaan H. Vinkers1, 2 and Berend Olivier1, 3 1 Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584CG Utrecht, The Netherlands 2 Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands 3 Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Correspondence should be addressed to Christiaan H. Vinkers,
[email protected] Received 7 July 2011; Revised 10 October 2011; Accepted 2 November 2011 Academic Editor: John Atack Copyright © 2012 C. H. Vinkers and B. Olivier. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the GABAA receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system.