Benzodiazepine Dependence

File, Sandra E.; Hitchcott, Paul Kenneth

doi:10.1007/978-1-349-11847-2_17

Cited by 8 publications

(4 citation statements)

References 38 publications

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“…In the same way as social separation, diazepam withdrawal was presently shown to have an anxiogenic effect in the EPM, also in agreement with previously reported results (Assieé t al., 1991;Begg et al, 2005;Bhattacharya et al, 1995;File and Hitchcott, 1991;Fontanesi et al, 2007;Martijena et al, 1996;Pokk and Zharkovsky, 1998;Souza Pinto et al, 2007;Wright et al, 1991). However, in the former studies the anxiogenic effect was observed 24-48 h after the last injection of diazepam, while in the present work the abstinence period was only 12 h. The behavioural changes induced by discontinuation of chronic diazepam seem to be time-dependent, because after 72 h they have been shown to disappear (Martijena et al, 1996).…”

Section: Discussioncontrasting

confidence: 53%

“…Abrupt withdrawal of a benzodiazepine (12, 24 or 48 h) following prolonged administration (7-21 days) has been shown to induce anxiety in rats or mice, measured in different animal models: plus-maze (Assie´et al, 1991;Bhattacharya et al, 1995;File and Hitchcott, 1991;Fontanesi et al, 2007;Martijena et al, 1996;Pokk and Zharkovsky, 1998;Wright et al, 1991), social interaction (Andrews and File, 1993;Andrews et al, 1997) or in both (Begg et al, 2005), and light-dark test (Souza Pinto et al, 2007). Withdrawal for 24 h from chronic diazepam treatment (21 days) has been related to increased 5-HT release in the hippocampus (Andrews and File, 1993;Andrews et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Social separation and diazepam withdrawal increase anxiety in the elevated plus-maze and serotonin turnover in the median raphe and hippocampus

2009

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The present work aimed to evaluate the effects of social separation for 14 days (chronic stress) and of withdrawal from a 14-day treatment with diazepam (acute stress) on the exploratory behaviour of male rats in the elevated plus-maze and on serotonin (5-hydroxytryptamine) turnover in different brain structures. Social separation had an anxiogenic effect, evidenced by fewer entries into, and less time spent on the open arms of the elevated plus-maze. Separation also selectively increased 5-hydroxytryptamine turnover in the hippocampus and median raphe nucleus. Diazepam withdrawal had a similar anxiogenic effect in grouped animals and increased 5-hydroxytryptamine turnover in the same brain structures. Chronic treatment with imipramine during the 14 days of separation prevented the behavioural and neurochemical changes caused by social separation. It is suggested that the increase in anxiety determined by both acute and chronic stress is mediated by the activation of the median raphe nucleus-hippocampal 5-hydroxytryptamine pathway.

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Section: Discussioncontrasting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Social separation and diazepam withdrawal increase anxiety in the elevated plus-maze and serotonin turnover in the median raphe and hippocampus

2009

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“…However, their usefulness in chronic therapy is limited by a combination of tolerance, side effects, abuse potential, and interaction with ethanol (File, 1993). Furthermore, withdrawal symptoms develop after prolonged exposure to BZs, and these symptoms may occur even after low to moderate doses (Gallager and Primus, 1993;Klein and Harris, 1996).…”

Section: Abstract: Withdrawal; Inhibitory Synapses; Drug Dependence;mentioning

confidence: 99%

Silent GABA_ASynapses during Flurazepam Withdrawal Are Region-Specific in the Hippocampal Formation

1997

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Whole-cell patch-clamp recordings were made from CA1 pyramidal and dentate gyrus granule cells (GCs) in hippocampal slices to assess the effects of withdrawal from chronic flurazepam (FRZ) treatment on the function of synaptic GABA A receptors. In slices from control rats, acute perfusion of FRZ (30 M) increased the monoexponential decay time constant of miniature IPSCs (mIPSCs) in CA1 and GCs (from 3.4 Ϯ 0.6 to 7.6 Ϯ 2.1 msec and from 4.2 Ϯ 0.6 to 7.1 Ϯ 1.8 msec, respectively) but did not change their mean conductance, 10 -90% rise time, or frequency of occurrence. Withdrawal (2-5 d) from chronic in vivo FRZ treatment (40 -110 mg/kg per day, per os) resulted in a dramatic loss of mIPSCs in CA1 neurons. On day 5 of withdrawal, no mIPSCs could be recorded in 40% of CA1 pyramidal cells. In the remaining 60% of the neurons, mIPSCs had a reduced mean conductance (from 0.78 Ϯ 0.12 nS in vehicle-treated controls to 0.31 Ϯ 0.05 nS) and a diminished frequency of occurrence (from 20.7 Ϯ 7.9 to 4.1 Ϯ 0.6 Hz). We have estimated that Ͼ80% of GABA A synapses on CA1 pyramidal cells had become silent, whereas at still-active synapses the number of functional GABA A receptor channels decreased by 60%. This reduction rapidly reverted to control levels on day 6 of withdrawal. FRZ withdrawal did not alter mIPSC properties in GCs. Our results are consistent with the hypothesis that chronic benzodiazepine treatment leads to a reduced number of functional synaptic GABA A receptors in a region-specific manner that may stem from differences in the subunit composition of synaptic GABA A receptors. Key words: withdrawal; inhibitory synapses; drug dependence; benzodiazepines; GABA A ; IPSCs; hippocampusBenzodiazepines (BZ) commonly are used as anxiolytic, antiepileptic, sedative hypnotic, and muscle relaxant agents. However, their usefulness in chronic therapy is limited by a combination of tolerance, side effects, abuse potential, and interaction with ethanol (File, 1993). Furthermore, withdrawal symptoms develop after prolonged exposure to BZs, and these symptoms may occur even after low to moderate doses (Gallager and Primus, 1993;Klein and Harris, 1996).During prolonged BZ treatment tolerance develops and is associated with the progressive loss of drug effectiveness. It implies an increase of the dose required to obtain therapeutic effects. Cessation of drug treatment produces a behavioral syndrome called withdrawal, which is characterized by agitation, anxiety, tremor, insomnia, or convulsions (Schoch et al., 1993); these symptoms can be relieved by readministering the drug, and therefore they define a state of drug dependence. Animal studies have revealed that withdrawal symptoms after the termination of chronic BZ treatment may be blocked by the application of BZ receptor antagonists Gallager, 1985, 1988).The loss of anticonvulsant activity after chronic BZ treatment is thought to be associated with an uncoupling of BZ and GABA binding at the level of GABA A receptors (Gallager et al., 1984;Marley and Gallager, 1989). In some stud...

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“…Gallager [personal communication] has also found that chronic stress produced a shift to the right in diazepam's dose-response curve. Previous experiments have found tolerance to the effect of diazepam (4 mg/kg) after 2 1 days of treatment and an anxiogenic response on withdrawal File, 1993) and in a study explicitly comparing the effects of different doses (1 and 2.5 mg/kg) on the rate of development of tolerance and withdrawal responses, tolerance developed more rapidly when chronic dosing was with the higher dose (File, 1989). Indeed, 4 mg/kg/day is not a particularly high dose of diazepam in the rat and other studies reporting anxiogenic withdrawal responses have used doses of diazepam as high as 240 mg/kg/day (Emmett-Oglesby et al, 1987).…”

Section: Discussionmentioning

confidence: 95%

Noise stress and the development of benzodiazepine dependence in the rat

File

Fernandes

1994

Anxiety

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Rats housed in conditions of noise stress were given daily injections of diazepam (4 mg/kg). Significant tolerance developed to the sedative effects within 5 days of treatment, as measured by head dipping and motor activity in the holeboard and by the number of closed arm entries in the plus-maze. These results are in agreement with other reports of rapid tolerance to sedative effects. However, in contrast to the usual finding of tolerance to anxiolytic actions after 2-3 weeks of treatment, in this study no tolerance developed after 23 days of treatment to diazepam's anxiolytic effects in the plus-maze. On withdrawal from the 23 days of diazepam treatment, there was no anxiogenic response in the plus-maze. Therefore, it seems that when chronic administration of diazepam is accompanied by chronic stress, tolerance does not occur to the anxiolytic effects, although it does develop to the sedative effects.

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Benzodiazepine Dependence

Cited by 8 publications

References 38 publications

Social separation and diazepam withdrawal increase anxiety in the elevated plus-maze and serotonin turnover in the median raphe and hippocampus

Social separation and diazepam withdrawal increase anxiety in the elevated plus-maze and serotonin turnover in the median raphe and hippocampus

Silent GABA_ASynapses during Flurazepam Withdrawal Are Region-Specific in the Hippocampal Formation

Noise stress and the development of benzodiazepine dependence in the rat

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Benzodiazepine Dependence

Cited by 8 publications

References 38 publications

Social separation and diazepam withdrawal increase anxiety in the elevated plus-maze and serotonin turnover in the median raphe and hippocampus

Social separation and diazepam withdrawal increase anxiety in the elevated plus-maze and serotonin turnover in the median raphe and hippocampus

Silent GABAASynapses during Flurazepam Withdrawal Are Region-Specific in the Hippocampal Formation

Noise stress and the development of benzodiazepine dependence in the rat

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Silent GABA_ASynapses during Flurazepam Withdrawal Are Region-Specific in the Hippocampal Formation