Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?. (29th March 2012)

• Record Type: Journal Article
• Authors: Vinkers, Christiaan H.; Olivier, Berend
• Other Names: Atack John Academic Editor.
• Is Part Of: Advances in pharmacological sciences. Volume 2012(2012)
• Publication Date: 2012-03-29
• Subjects: Pharmacology -- Periodicals; Pharmacological Phenomena; Pharmacology; Periodicals; 615.1
• DOI: 10.1155/2012/416864
• Languages: English
• ISSNs: 1687-6334

Abstract

Abstract : 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) theGABA A 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. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance-inducing mechanism depends on the activatedGABA A receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site.