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 Mice withdrawn from chronic treatment with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.