RT Journal Article
SR Electronic
T1 Antagonist-Induced Reversal of Functional and Structural Measures of Hippocampal Benzodiazepine Tolerance
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 932
OP 942
VO 291
IS 3
A1 Tietz, Elizabeth I.
A1 Zeng, Xu J.
A1 Chen, Shanyi
A1 Lilly, Scott M.
A1 Rosenberg, Howard C.
A1 Kometiani, Peter
YR 1999
UL http://jpet.aspetjournals.org/content/291/3/932.abstract
AB One week oral flurazepam (FZP) administration in rats results in anticonvulsant tolerance in vivo, tolerance measured in vitro in hippocampal CA1 pyramidal cells, and regulation of hippocampal γ-aminobutyric acidA-receptor subunit protein expression. A single injection (4 or 20 mg/kg i.p) of the benzodiazepine antagonist flumazenil (FLM) was given 1 day after FZP treatment, and tolerance and subunit protein expression were evaluated 1 day later. In vivo tolerance was measured by a reduced ability of the α1-subunit-selective agonist zolpidem to suppress pentylenetetrazole-induced seizures. This tolerance was reversed by 20 but not 4 mg/kg FLM. In in vitro hippocampal slices, there was tolerance to the effect of zolpidem to prolong the decay of pyramidal cell miniature inhibitory postsynaptic currents, which was reversed by FLM (4 mg/kg) pretreatment. A reduction in miniature inhibitory postsynaptic current amplitude (∼50%) was also restored by FLM injection. [3H]Zolpidem binding measured 0, 2, and 7 days after FZP treatment was significantly decreased in the hippocampus and cortex at 0 days but not thereafter. Changes in α1- and β3-subunit protein expression were examined via quantitative immunohistochemical techniques. α1-Subunit protein levels were down-regulated in the CA1 stratum oriens and β subunit levels were up-regulated in the stratum oriens and stratum radiatum of the CA3 region. Chronic FZP effects on α1- and β3-subunit protein levels were also reversed by prior FLM injection. FLM's effect on both functional and structural correlates of benzodiazepine tolerance suggests that each of these measures plays an interdependent role in mediating benzodiazepine tolerance. The American Society for Pharmacology and Experimental Therapeutics