DIAZEPAM DEPENDENCE PREVENTED BY GLUTAMATE ANTAGONISTS

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 Mice withdrawn from chronic treat ment with diazepam showed a time-related evolution of anxiety, muscle rigidity, and seizures between days 4 and 21 after treatment discontin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.