Use of the specific benzodiazepine antagonist, Ro 15-1788, in studies of physiological dependence on benzodiazepines

Cumin, R.; Bonetti, E. P.; Scherschlicht, R.; Haefely, W.

doi:10.1007/bf01972300

Cited by 92 publications

(16 citation statements)

References 5 publications

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“…The results of experiment 4 are consistent with such an interpretation, since RO 15-1788 would be expected to reverse the withdrawal reaction if administered at the same time as lorazepam (thereby preventing the initial benzodiazepine effect). The results of experiment 3 also fit the withdrawal hypothesis, since RO 15-1788 would not be expected to reverse the reaction if administered at the later time, but might, if the benzodiazepine was still present and exerting an effect, exacerbate it (Lukas and Griffiths 1982;Rosenberg and Chiu 1982;Cumin et al 1982). In the present study RO 15-1788 did not exacerbate the hypoactivity.…”

Section: Discussionsupporting

confidence: 51%

A late-appearing benzodiazepine-induced hypoactivity that is not reversed by a receptor antagonist

Lister

File

1986

Psychopharmacology

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The activity of rats in a holeboard test is reduced 30, 90, and 240 min after treatment with a single dose of lorazepam. The administration of a benzodiazepine antagonist (RO 15-1788) 20 min before the holeboard test (i.e., 10, 70, or 220 min after lorazepam administration) reverses the hypoactivity of animals tested 30 min after treatment with lorazepam, partially reverses the hypoactivity of animals tested 90 min after receiving lorazepam, but is without effect on the hypoactivity observed 240 min after treatment with the benzodiazepine. If, however, RO 15-1788 is given at the same time as lorazepam then it reverses the hypoactivity seen 4 h later. The results of these experiments demonstrate that a benzodiazepine can exert a behavioral effect at a time when it no longer appears to be acting at central benzodiazepine receptors.

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Section: Discussionsupporting

confidence: 51%

A late-appearing benzodiazepine-induced hypoactivity that is not reversed by a receptor antagonist

Lister

File

1986

Psychopharmacology

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“…Recent studies indicated that benzodiazepine treatment shows evidence of dependence (Hallstrom and Lader 1981 ;Petursson and Lader 1981 ;Tyrer et al 1983) and withdrawal reactions on abrupt termination of chronic diazepam treatment in both humans and animals (Murphy et al 1984;Martin et al 1982). It was also observed that treatment with Ro 15-1788, a benzodiazepine receptor antagonist, precipitated withdrawal symptoms in baboons (Lamb and Griffiths 1985) and in rats (Cumin et al 1982;Lukas and Griffiths 1982), indicating a physiological role of benzodiazepine receptors in the development of dependence.…”

mentioning

confidence: 93%

Reversal by alpha-2 agonists of diazepam withdrawal hyperactivity in rats

Kunchandy

1986

Psychopharmacology

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Rats were made diazepam dependent by chronic treatment with daily injections of the drug, 20 mg/kg, IP, for 3 weeks. On abrupt termination of the drug, the animals showed withdrawal hyperactivity which was indicated by increased horizontal locomotion and vertical activity, and diarrhoea. The peak effect was seen 3 days after the withdrawal of diazepam. Effects of various alpha 2 agonists, clonidine, guanfacine and B-HT 920, were studied on the diazepam withdrawal phenomena. Clonidine (100 micrograms/kg, IP) given twice a day at an interval of 12 h prevented both withdrawal-induced hyperactivity and diarrhoea. On the contrary, equimolar doses of guanfacine and B-HT 920 failed to reverse withdrawal-induced hyperactivity but attenuated the effect of diarrhoea. However, higher doses (500 micrograms/kg, IP) of guanfacine and B-HT 920 given twice a day at 12-h intervals were found to be effective. Pretreatment with yohimbine (1.5 mg/kg, IP) reversed the protective effect of clonidine, indicating the involvement of alpha 2 receptors in the action of clonidine.

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“…While rats chronically treated with 10 or 100 mg/ kg of diazepam, for 12 days, failed to display precipitated seizures after i.p. administration of flumazenil (10 mg/ kg), the same dose of flumazenil precipitated seizures in monkeys treated for 15 days with only 10mg/kg of diazepam (Cumin et al, 1982). Also, although precipitated withdrawal seizures have not been observed in rats after i.p.…”

Section: Discussionmentioning

confidence: 97%

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

Baldwin

Hitchcott

File

1990

Human Psychopharmacology

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Rats were treated with diazepam (4 mg/kg per day) or its vehicle for 21 days. Twentyâ\u80\u90four hours after their last dose they were tested in the social interaction test of anxiety. Diazepam withdrawal significantly reduced the time spent in social interaction compared with controls, indicating an anxiogenic withdrawal response. The administration of a single dose of flumazenil (4 mg/kg) during chronic diazepam treatment, 7 or 14 days before testing, prevented the development of this withdrawal response. The clinical implications of these findings are discussed. Copyright Â© 1990 John Wiley & Sons, Ltd

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Use of the specific benzodiazepine antagonist, Ro 15-1788, in studies of physiological dependence on benzodiazepines

Cited by 92 publications

References 5 publications

A late-appearing benzodiazepine-induced hypoactivity that is not reversed by a receptor antagonist

A late-appearing benzodiazepine-induced hypoactivity that is not reversed by a receptor antagonist

Reversal by alpha-2 agonists of diazepam withdrawal hyperactivity in rats

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

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