Chronic benzodiazepine treatment does not alter interactions between positive GABA(A) modulators and flumazenil or pentylenetetrazole in monkeys.
Chronic benzodiazepine treatment does not alter interactions between positive GABA(A) modulators and flumazenil or pentylenetetrazole in monkeys.
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DOI：
10.1097/fbp.0b013e3283425aa0
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发表时间：
2011-02
影响因子：
1.6
通讯作者：
France CP
中科院分区：
文献类型：
--
作者：
Gerak LR;France CP
Benzodiazepines and neuroactive steroids are positive GABAA modulators acting at distinct binding sites; during benzodiazepine treatment, tolerance develops to many behavioral effects of benzodiazepines, although cross tolerance does not develop to neuroactive steroids. To determine whether differential changes in binding sites contribute to these behavioral differences, interactions between GABAA modulators were studied in two groups of four monkeys: one group discriminated 0.178 mg/kg of the benzodiazepine midazolam; the other received 5.6 mg/kg/day diazepam and discriminated 0.1 mg/kg flumazenil, which binds to benzodiazepine sites without modulating GABAA receptors. In untreated monkeys, flumazenil antagonized midazolam but not the neuroactive steroid pregnanolone, while pentylenetetrazole (a negative modulator acting at a third site) antagonized both positive modulators. In diazepam-treated monkeys, 0.1 mg/kg flumazenil or 32 mg/kg pentylenetetrazole produced flumazenil-lever responding, which was reversed by midazolam and pregnanolone. As flumazenil dose increased, larger doses of midazolam, but not pregnanolone, were needed to reverse flumazenil-lever responding. When the pentylenetetrazole dose increased, larger doses of both positive modulators were needed. Thus, interactions between GABAA modulators were not different between diazepam-treated and untreated monkeys and do not reveal changes in binding sites that could account for differences between benzodiazepines and neuroactive steroids.
