DIAZEPAM DEPENDENCE PREVENTED BY GLUTAMATE ANTAGONISTS

Citation
Kg. Steppuhn et L. Turski, DIAZEPAM DEPENDENCE PREVENTED BY GLUTAMATE ANTAGONISTS, Proceedings of the National Academy of Sciences of the United Statesof America, 90(14), 1993, pp. 6889-6893
Citations number
17
Categorie Soggetti
Multidisciplinary Sciences
ISSN journal
00278424
Volume
90
Issue
14
Year of publication
1993
Pages
6889 - 6893
Database
ISI
SICI code
0027-8424(1993)90:14<6889:DDPBGA>2.0.ZU;2-Y
Abstract
Long-term treatment leads to tolerance to and dependence on benzodiaze pines. Abrupt termination of benzodiazepine administration triggers th e expression of signs of dependence. Mice withdrawn from chronic treat ment with diazepam showed a time-related evolution of anxiety, muscle rigidity, and seizures between days 4 and 21 after treatment discontin uation. A period between withdrawal days 1 and 3 was symptom-free. Sur prisingly, during this ''silent phase'' the susceptibility of mice to 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 contra st, the ''active phase'', between withdrawal days 4 and 21, was charac terized by increased susceptibility to NMDA seizures and enhanced magn itude of polysynaptic reflexes, which are NMDA dependent. Treatment of mice with pha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) a ntagonists, -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 5 2466) or 3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline but not wi th the NMDA antagonist +/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphon ate (CPP) during the silent phase prevented signs of dependence. In co ntrast, treatment with CPP but not with GYKI 52466 during the active p hase prevented the symptoms. The development of tolerance to and depen dence on diazepam was prevented by concurrent treatment of mice with C PP but was not prevented by GYKI 52466. These data indicate that NMDA- dependent mechanisms contribute to the development of tolerance to dia zepam and to the expression of signs of dependence in mice after termi nation of long-term treatment with diazepam. Nevertheless, the non-NMD A-mediated silent phase is essential for triggering the symptoms. Ther efore, AMPA antagonists may offer a therapeutic approach for preventin g dependence on benzodiazepines that is an alternative to NMDA antagon ism.