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
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 Mice withdrawn from chronic treat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.