Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?
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 t...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2012-01-01
|
| Series: | Advances in Pharmacological Sciences |
| Online Access: | http://dx.doi.org/10.1155/2012/416864 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832562920799600640 |
|---|---|
| author | Christiaan H. Vinkers Berend Olivier |
| author_facet | Christiaan H. Vinkers Berend Olivier |
| author_sort | Christiaan H. Vinkers |
| collection | DOAJ |
| description | 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. 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 activated GABAA receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site. |
| format | Article |
| id | doaj-art-f9511fcd49de4483984ec51c8da6f8e0 |
| institution | Kabale University |
| issn | 1687-6334 1687-6342 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advances in Pharmacological Sciences |
| spelling | doaj-art-f9511fcd49de4483984ec51c8da6f8e02025-02-03T01:21:35ZengWileyAdvances in Pharmacological Sciences1687-63341687-63422012-01-01201210.1155/2012/416864416864Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?Christiaan H. Vinkers0Berend Olivier1Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584CG Utrecht, The NetherlandsDivision of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584CG Utrecht, The NetherlandsDespite 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. 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 activated GABAA receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site.http://dx.doi.org/10.1155/2012/416864 |
| spellingShingle | Christiaan H. Vinkers Berend Olivier Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators? Advances in Pharmacological Sciences |
| title | Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective
GABAA Receptor Modulators? |
| title_full | Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective
GABAA Receptor Modulators? |
| title_fullStr | Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective
GABAA Receptor Modulators? |
| title_full_unstemmed | Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective
GABAA Receptor Modulators? |
| title_short | Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective
GABAA Receptor Modulators? |
| title_sort | mechanisms underlying tolerance after long term benzodiazepine use a future for subtype selective gabaa receptor modulators |
| url | http://dx.doi.org/10.1155/2012/416864 |
| work_keys_str_mv | AT christiaanhvinkers mechanismsunderlyingtoleranceafterlongtermbenzodiazepineuseafutureforsubtypeselectivegabaareceptormodulators AT berendolivier mechanismsunderlyingtoleranceafterlongtermbenzodiazepineuseafutureforsubtypeselectivegabaareceptormodulators |