The use of flumazenil in prevention of Diazepam dependence in the rat

Baldwin, Helen A.; Hitchcott, Paul Kenneth; File, Sandra E.

doi:10.1002/hup.470050109

Cited by 18 publications

(12 citation statements)

References 18 publications

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“…These, and other Þndings have subsequently been interpreted as evidence that chronic benzodiazepine administration results in an adaptation of the GABA / benzodiazepine receptor complex which administration of ßumazenil is able to reset (Nutt and Costello 1988;Sannerud et al 1989;Baldwin et al 1990). The present Þndings might suggest that simply the experience of withdrawal is the important factor in protecting against the anxiogenic e¤ects of subsequent withdrawals, and that the implication of ßumazenil in the phenomenon is incidental.…”

Section: Exptmentioning

confidence: 91%

Sensitisation of withdrawal signs following repeated withdrawal from a benzodiazepine: differences between measures of anxiety and seizure sensitivity

Ward

Stephens

1998

Psychopharmacology

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Three experiments examined the effect of either withdrawal from diazepam, or repeated treatment with the convulsant, pentylenetetrazol (PTZ), on behaviour and seizure threshold. The behaviours measured were on the elevated plus maze and in the four-plate test; seizure threshold was measured as dose of PTZ infused via the tail vein to the first clonic twitch. In experiment 1, we examined the effect of either single or repeated withdrawal from diazepam using a procedure in which the drug was administered SC in a slow release depot. Three cycles of withdrawal from diazepam were compared to a single withdrawal experience. A single withdrawal from diazepam following chronic treatment gave rise, 72 h following the last dosing, to behavioural changes, suggestive of anxiety, in both tests, but did not result in a reduced convulsant threshold. In contrast, repeated withdrawal resulted in a reduction in sensitivity in several measures of anxiety, but sensitised the mice to the convulsive effects of the PTZ. The unexpected failure to find an increased sensitivity to a convulsive agent following a single withdrawal from SC diazepam was examined in experiment 2. The seizure threshold following a single withdrawal of mice which had received diazepam chronically IP in aqueous vehicle was significantly reduced relative to vehicle-treated controls, whereas that of animals receiving the same dose SC in oil, was not. It is argued that the difference may arise from the animals treated repeatedly with IP diazepam unintentionally experiencing repeated withdrawal, since the half-life of the drug by this route is short. In experiment 3, repeated sub-convulsant PTZ treatment reduced the convulsant threshold (the dose of PTZ required to give rise to the first clonic twitch), but had no significant effect on the behavioural measures of anxiety compared to a single dose of PTZ or vehicle controls. The results suggest that repeated withdrawal from chronic treatments with diazepam sensitises mice to convulsant stimuli in a manner resembling the effects of repeated administration of sub-convulsant doses of PTZ, but that neither repeated PTZ nor repeated diazepam withdrawal results in increased sensitivity to anxiogenic stimuli; rather, repeated withdrawal from diazepam may reduce the susceptibility of mice to behavioural measures of anxiety.

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Section: Exptmentioning

confidence: 91%

Sensitisation of withdrawal signs following repeated withdrawal from a benzodiazepine: differences between measures of anxiety and seizure sensitivity

Ward

Stephens

1998

Psychopharmacology

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“…In contrast, other studies (Baldwin and File 1989;Baldwin et al 1990), including studies in non-human primates (Lamb and Griffiths 1985;Gallager et al 1986), have demonstrated that exposure to flumazenil can attenuate the subsequent effects of flumazenil. For example, in rhesus monkeys treated daily with either 1.5 or 6.0 mg/kg diazepam (IM.…”

Section: Discussionmentioning

confidence: 76%

“…It has been suggested that this adverse consequence of long-term benzodiazepine use has influenced the frequency with which this class of drugs is prescribed and administered; thus, strategies to prevent the development of dependence might increase the clinical utility of benzodiazepines (Rickels et al 1983). Several preclinical studies have suggested that occasional exposure to flumazenil might retard the development of dependence, as evidenced by the reduced effectiveness of flumazenil in precipitating withdrawal signs in benzodiazepine-treated subjects (Lamb and Griffiths 1985;Gallager et al 1986;Baldwin and File 1989;Baldwin et al 1990); however, the generality of this finding has yet to be established. On the one hand, the failure of the current study to replicate previous reports suggests that the particular conditions under which the effects of benzodiazepine antagonists are assessed critically determine whether these effects change over time; on the other hand, the ability to reliably determine quantitatively similar dose-effect curves for flumazenil in benzodiazepine-treated monkeys suggests that other behavioral procedures, that require the frequent administration of antagonists, might be useful for studying benzodiazepines and that changes in sensitivity to the behavioral effects of flumazenil could be further exploited to study benzodiazepine dependence and withdrawal.…”

Section: Discussionmentioning

confidence: 98%

“…For example, in rats, rhesus monkeys and baboons treated chronically with a benzodiazepine, flumazenil precipitates a characteristic withdrawal syndrome. However, the frequency and magnitude of withdrawal signs diminish markedly upon subsequent administration of flumazenil (Lamb and Griffiths 1985;Gallager et al 1986;Baldwin and File 1989;Baldwin et al 1990). If a reduced effectiveness of flumazenil over repeated administration also occurs in humans, then periodic treatment with flumazenil might have some utility in modifying the development or expression of dependence.…”

Section: Methodsmentioning

confidence: 97%

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Repeated administration of flumazenil does not alter its potency in modifying schedule-controlled behavior in chlordiazepoxide-treated rhesus monkeys

Gerak

1997

Psychopharmacology

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Previous reports have suggested that the effects of the benzodiazepine antagonist flumazenil diminish over repeated exposure in subjects treated chronically with a benzodiazepine agonist. The current study examined whether the frequency of exposure to flumazenil altered its potency in decreasing rates of responding in monkeys treated with chlordiazepoxide (CDP). Three monkeys responded under a multiple fixed ratio (FR10:FR10) schedule of food presentation and stimulus-shock termination (SST). In untreated monkeys, flumazenil (0.1-3.2 mg/kg) had no effect in either component. After 2 weeks of treatment with 32.0 mg/kg per day of CDP, flumazenil decreased response rates in the food component, with a dose of 3.2 mg/kg decreasing rates to 10% of control; rates in the SST component were not altered by flumazenil. When flumazenil dose-effect curves were redetermined at 28-, 14-, 7-, 4-, 2- or 1-day intervals, there was no further change in the potency of flumazenil in decreasing food-maintained responding. When CDP treatment was terminated, the potency of flumazenil recovered to pre-CDP values within 23 days. These results suggest that dependence develops to CDP, since changes in the potency of flumazenil co-varied with CDP treatment. Moreover, it does not appear as though results from previous reports, that showed a diminished response to frequently-administered flumazenil, can be generalized to all conditions.

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“…This effect can be reversed by a single injection of the benzodiazepine antagonist, flumazenil (Gonsalves and Gallager, 1985;Nutt and Costello, 1988). Repeated administration of flumazenil prevents benzodiazepine withdrawal signs in Rhesus monkeys (Gallager, Heninger and Heninger, 1986), and even a single dose can prevent diazepam dependence in the rat (Baldwin, Hitchcott and File, 1990). However, two studies using flumazenil suggest that tolerance and physical dependence may be distinct phenomena with the benzodiazepines (Lamb and Griffiths, 1985;Loscher and Rundfeldt, 1989).…”

Section: Introductionmentioning

confidence: 95%

Lack of effect of a small dose of flumazenil in reversing short-term tolerance to benzodiazepines in normal subjects

Cittadini

Lader

1991

J Psychopharmacol

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Twelve normal volunteers received two courses of 7 days of either lorazepam (2 mg every morning; six subjects) or oxazepam (30 mg every morning; six subjects). After one of the courses, 0.2 mg of flumazenil was injected, after the other placebo, using a balanced design and double-blind procedures. A test dose of the lorazepam or oxazepam was administered the day after the flumazenil or placebo. A battery of physiological and psychological tests was applied before and after the dose of benzodiazepine on days 1, 4, 8 and 10. The benzodiazepines had the expected effects on the EEG, and event-related potentials (ERP), impaired several psychological tests and induced drowsiness and relaxation. Some tolerance was seen with respect to anxiolytic effects, some EEG and ERP variables and some psychological tests, but not those of memory. Tolerance tended to be more apparent in the subjects given lorazepam than in the oxazepam-treated subjects. No effects of the small dose of flumazenil in reversing tolerance were apparent.

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The use of flumazenil in prevention of Diazepam dependence in the rat

Cited by 18 publications

References 18 publications

Sensitisation of withdrawal signs following repeated withdrawal from a benzodiazepine: differences between measures of anxiety and seizure sensitivity

Sensitisation of withdrawal signs following repeated withdrawal from a benzodiazepine: differences between measures of anxiety and seizure sensitivity

Repeated administration of flumazenil does not alter its potency in modifying schedule-controlled behavior in chlordiazepoxide-treated rhesus monkeys

Lack of effect of a small dose of flumazenil in reversing short-term tolerance to benzodiazepines in normal subjects

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