Posted by medievil on January 17, 2007, at 12:23:09
its time for ppl to try an NMDA antagonist for benzo's, some ppl have no problems with tolerance but others do!! so this might be the solution for them!!!
NMDA recepter really is the tolerance bad guy!!Effect of NMDA antagonists on rapid tolerance to benzodiazepines.
* Khanna JM,
* Chau A,
* Shah G.Department of Pharmacology, University of Toronto, Canada.
We have reexamined the effect of NMDA antagonists [(+)MK-801 and ketamine] on rapid tolerance to chlordiazepoxide. (+)MK-801 and ketamine blocked the development of rapid tolerance to chlordiazepoxide, but this effect was dependent on the dose ratio of the NMDA antagonist to that of the benzodiazepine used to produce rapid tolerance. Furthermore, NMDA antagonists blocked both learned and unlearned tolerance to chlordiazepoxide. It appears that in addition to impairment of memory and learning, NMDA antagonists may also influence some other mechanism involved in the production of drug-tolerance.
Diazepam dependence prevented by glutamate antagonists.
* Steppuhn KG,
* Turski L.Research Laboratories of Schering AG, Berlin, Germany.
Long-term treatment leads to tolerance to and dependence on benzodiazepines. Abrupt termination of benzodiazepine administration triggers the expression of signs of dependence. Mice withdrawn from chronic treatment with diazepam showed a time-related evolution of anxiety, muscle rigidity, and seizures between days 4 and 21 after treatment discontinuation. A period between withdrawal days 1 and 3 was symptom-free. Surprisingly, during this "silent phase" the susceptibility of mice to alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate (ATPA) and kainate seizures and the magnitude of monosynaptic reflexes mediated by non-N-methyl-D-aspartate (NMDA) mechanisms were enhanced. In apparent contrast, the "active phase", between withdrawal days 4 and 21, was characterized by increased susceptibility to NMDA seizures and enhanced magnitude of polysynaptic reflexes, which are NMDA dependent. Treatment of mice with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) or 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline but not with the NMDA antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) during the silent phase prevented signs of dependence. In contrast, treatment with CPP but not with GYKI 52466 during the active phase prevented the symptoms. The development of tolerance to and dependence on diazepam was prevented by concurrent treatment of mice with CPP but was not prevented by GYKI 52466. These data indicate that NMDA-dependent mechanisms contribute to the development of tolerance to diazepam and to the expression of signs of dependence in mice after termination of long-term treatment with diazepam. Nevertheless, the non-NMDA-mediated silent phase is essential for triggering the symptoms. Therefore, AMPA antagonists may offer a therapeutic approach for preventing dependence on benzodiazepines that is an alternative to NMDA antagonism.
poster:medievil
thread:723215
URL: http://www.dr-bob.org/babble/20070113/msgs/723215.html