Evidence against oppositional and pharmacokinetic mechanisms of tolerance to diazepam's sedative effects

Fernandes, Cathy; File, Sandra E.; Berry, Dave

doi:10.1016/0006-8993(96)00644-0

Cited by 25 publications

(10 citation statements)

References 27 publications

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“…Loss of sedative efficacy of diazepam with chronic treatment has been proposed to result from the development of adaptive processes counteracting the repeated enhancement by the benzodiazepine of GABA A receptor-mediated inhibitory neurotransmission (Steppuhn and Turski, 1993;File and Fernandes, 1994;Fernandes et al, 1996;Marin et al, 1996Marin et al, , 1999Perez et al, 2003). Functional alterations of GABA A receptors have frequently been reported after various chronic treatment regimens with diazepam (Hutchinson et al, 1996;Itier et al, 1996;Primus et al, 1996;Ali and Olsen, 2001;Costa et al, 2001;Bateson, 2002).…”

Section: Introductionmentioning

confidence: 99%

Requirement of α₅-GABA_AReceptors for the Development of Tolerance to the Sedative Action of Diazepam in Mice

Rijnsoever¹,

Täuber²,

Choulli³

et al. 2004

J. Neurosci.

132

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Despite its pharmacological relevance, the mechanism of the development of tolerance to the action of benzodiazepines is essentially unknown. The acute sedative action of diazepam is mediated via ␣ 1 -GABA A receptors. Therefore, we tested whether chronic activation of these receptors by diazepam is sufficient to induce tolerance to its sedative action. Knock-in mice, in which the ␣ 1 -, ␣ 2 -, ␣ 3 -, or ␣ 5 -GABA A receptors had been rendered insensitive to diazepam by histidine-arginine point mutation, were chronically treated with diazepam (8 d;) and tested for motor activity. Wild-type, ␣ 2 (H101R), and ␣ 3 (H126R) mice showed a robust diminution of the motor-depressant drug action. In contrast, ␣ 5 (H105R) mice failed to display any sedative tolerance. ␣ 1 (H101R) mice showed no alteration of motor activity with chronic diazepam treatment. Autoradiography with [ 3 H]flumazenil revealed no change in benzodiazepine binding sites. However, a decrease in ␣ 5 -subunit radioligand binding was detected selectively in the dentate gyrus with specific ligands. This alteration was observed only in diazepam-tolerant animals, indicating that the manifestation of tolerance to the sedative action of diazepam is associated with a downregulation of ␣ 5 -GABA A receptors in the dentate gyrus. Thus, the chronic activation of ␣ 5 -GABA A receptors is crucial for the normal development of sedative tolerance to diazepam, which manifests itself in conjunction with ␣ 1 -GABA A receptors.

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Section: Introductionmentioning

confidence: 99%

Requirement of α₅-GABA_AReceptors for the Development of Tolerance to the Sedative Action of Diazepam in Mice

Rijnsoever¹,

Täuber²,

Choulli³

et al. 2004

J. Neurosci.

132

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“…13.7 ± 1.6 42.9 ± 3.6 54.7 ± 6.6 107.2 ± 7.9 PTMB (10) 11.3 ± 1.8 37.3 ± 2.8 43.8 ± 3.6 103.7 ± 8.9 PTMB (30) 9.7 ± 1.8* 39.0 ± 3.4 44.4 ± 5.3 116.6 ± 11.0 cific motor activity in rodents (5,11,13). In the holeboard, 2 mg/kg picrotoxin significantly decreased the number of head dips, the time spent head dipping, the number of rearing responses and the number of squares crossed with all paws.…”

Section: Picrotoxinmentioning

confidence: 99%

“…Statistical analysis of the latency to fall from the rotarod revealed that diazepam (1 mg/kg) and PTMB (3, 10 and 30 mg/kg) produced significant motor incoordination compared to vehicle control (F(4,70) = 7.6; P<0.001; Figure 2). The holeboard test has been claimed to be suitable to assess directed exploratory behavior, since it allows the discrimination between exploratory activity and nonspe- 10.1 ± 2.5 36.8 ± 3.6 42.6 ± 6.5 158.7 ± 16.8* Vehicle 16.4 ± 2.2 40.9 ± 2.9 45.6 ± 2.5 107.9 ± 11.6 PTMB (0.3) 17.5 ± 3.0 38.7 ± 2.3 42.0 ± 3.5 106.1 ± 9.6 PTMB (1.0)18.4 ± 2.3 43.0 ± 2.8 51.1 ± 3.6 105.4 ± 10.5 PTMB (3.0)13.7 ± 1.6 42.9 ± 3.6 54.7 ± 6.6 107.2 ± 7.9 PTMB (10) 11.3 ± 1.8 37.3 ± 2.8 43.8 ± 3.6 103.7 ± 8.9 PTMB (30) 9.7 ± 1.8* 39.0 ± 3.4 44.4 ± 5.3 116.6 ± 11.0 cific motor activity in rodents (5,11,13). In the holeboard, 2 mg/kg picrotoxin significantly decreased the number of head dips, the time spent head dipping, the number of rearing responses and the number of squares crossed with all paws.…”

mentioning

confidence: 99%

“…The holeboard test has been claimed to be suitable to assess directed exploratory behavior, since it allows the discrimination between exploratory activity and nonspe- cific motor activity in rodents (5,11,13). In the holeboard, 2 mg/kg picrotoxin significantly decreased the number of head dips, the time spent head dipping, the number of rearing responses and the number of squares crossed with all paws.…”

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confidence: 99%

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Anxiolytic-like effects of 4-phenyl-2-trichloromethyl-3H-1,5-benzodiazepine hydrogen sulfate in mice

Rubin

Albach

Berlese

et al. 2000

Braz J Med Biol Res

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The pharmacological effects of 4-phenyl-2-trichloromethyl-3H-1,5-benzodiazepine hydrogen sulfate (PTMB), a novel synthetic benzodiazepine, were examined in mice. In the elevated plus-maze test of anxiety, 0.3-1 mg/kg diazepam ip (F(3,53) = 3.78; P<0.05) and 1-10 mg/kg PTMB ip increased (F(5,98) = 3.26; P<0.01), whereas 2 mg/kg picrotoxin ip decreased (F(3,59) = 8.32; P<0.001) the proportion of time spent in the open arms, consistent with an anxiolytic action of both benzodiazepines, and an anxiogenic role for picrotoxin. In the holeboard, 1.0 mg/kg diazepam ip increased (F(3,54) = 2.78; P<0.05) and 2 mg/kg picrotoxin ip decreased (F(3,59) = 4.69; P<0.01) locomotor activity. Rotarod assessment revealed that 1 mg/kg diazepam ip and 3, 10 and 30 mg/kg PTMB ip produced significant motor incoordination compared to vehicle control (F(4,70) = 7.6; P<0.001). These data suggest that the recently synthesized PTMB compound possesses anxiolytic activity and produces motor incoordination similar to those observed with diazepam. PicrotoxinBenzodiazepine compounds have been reported to be the most extensively consumed psychoactive drugs worldwide due to their anxiolytic and anticonvulsant activity. However, undesirable side effects like muscle relaxation, sedation, physical dependence, tolerance, ataxia and memory impairment have been associated with the use of benzodiazepines. A variety of novel agents capable of interacting with benzodiazepine receptors have been investigated in order to develop non-sedative anxioselective agents (1-3). Two main hypotheses for the development of such anxioselective drugs have been proposed. The first suggests that different benzodiazepine receptor subtypes may be responsible for the behavioral effects of benzodiazepine compounds. According to this hypothesis, two receptor subtypes, benzodiazepine (omega) 1 and benzodiazepine (omega) 2 receptors, exist in different brain areas responsible for different physiological functions (2). The alternative hypothesis proposes the development of benzodiazepine receptor partial agonists which present lower intrinsic efficacy sufficient to maintain the anxiolytic and anticonvulsant responses, but insufficient to induce the side effects seen with full agonists (2,4). Most of the benzodiazepines used in clinical therapeutics are 1,4-benzodiazepines (5-7), since several products were generated by introducing substituents at different positions of the benzodiazepine ring of diazepam. Modifications in the structure of the ring have also been made, and the anxiolytic effect of 1,5-benzodiazepines (clobazam) has been described (8,9). However, considerably less is known about the effects of substituents on 1,5-benzodiazepines compared to the 1,4 group. In the present study we investigated the anxiolytic potential of the recently synthesized 4-phenyl-2-trichloromethyl-3H-1,5-benzodiazepine hydrogen sulfate (PTMB) (10). The effects of this new benzodiazepine on spontaneous coordinated motor movements were also evaluated.Male albino mice (35-40 g) from our ...

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“…Toutefois, des effets indésirables comme la dépendance physique, la tolérance, l'ataxie et le trouble de mémoire ont été associés à leur utilisation. La plupart des benzodiazépines utilisées en clinique thérapeutique sont issus de la classe de la 1,4-benzodiazépine (Fernandes et al, 1996;Zangrossi et al, 1999), puisque plusieurs produits ont été obtenus par l'introduction des substituants en différentes positions de cette dernière, et voir même par modification de la structure de l'anneau. Les effets anxiolytique et anticonvulsivant de 1,5-benzodiazépine (clobazam) ont été décrits (De Sarro et al, 1992;Remy, 1994 ;Widlocher, 2002;Perlemuter, 2008).…”

Section: Introductionunclassified

Évaluation de l’activité anxiolytique de la 4-phenyl-1,5-benzodiazepin-2-one

Kanyonga¹,

Faouzi²,

Zellou³

et al. 2009

International Journal of Biological and Chemical Sciences

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RESUMELes effets pharmacologiques de la 4-phenyl-1,5-benzodiazepin-2-one ont été examinés chez des souris par des tests comportementaux classiques (Test de planche à trous, Test de labyrinthe et Test de la tige tournante) et comparés par rapport aux produits dont le potentiel anxiogenique ou anxiolytique sont connus. L'analyse de nos résultats a montré que la 4-phenyl-1,5-benzodiazepin-2-one et le diazépam ont augmenté le temps passé dans les bras ouverts, tandis que la picrotoxin a entraîné la diminution de ce temps. Considérant les résultats de l'évaluation de l'activité locomotrice, du comportement exploratoire et du comportement des animaux sur la tige tournante, le diazépam et la 4-phenyl-1,5-benzodiazepin-2-one ont influencé de façon significative ces derniers par rapport à la picrotoxin et au véhicule. Ces données suggèrent que la 4-phenyl-1,5-benzodiazepin-2-one possède une activité anxiolytique.

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Evidence against oppositional and pharmacokinetic mechanisms of tolerance to diazepam's sedative effects

Cited by 25 publications

References 27 publications

Requirement of α₅-GABA_AReceptors for the Development of Tolerance to the Sedative Action of Diazepam in Mice

Requirement of α₅-GABA_AReceptors for the Development of Tolerance to the Sedative Action of Diazepam in Mice

Anxiolytic-like effects of 4-phenyl-2-trichloromethyl-3H-1,5-benzodiazepine hydrogen sulfate in mice

Évaluation de l’activité anxiolytique de la 4-phenyl-1,5-benzodiazepin-2-one

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Evidence against oppositional and pharmacokinetic mechanisms of tolerance to diazepam's sedative effects

Cited by 25 publications

References 27 publications

Requirement of α5-GABAAReceptors for the Development of Tolerance to the Sedative Action of Diazepam in Mice

Requirement of α5-GABAAReceptors for the Development of Tolerance to the Sedative Action of Diazepam in Mice

Anxiolytic-like effects of 4-phenyl-2-trichloromethyl-3H-1,5-benzodiazepine hydrogen sulfate in mice

Évaluation de l’activité anxiolytique de la 4-phenyl-1,5-benzodiazepin-2-one

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Requirement of α₅-GABA_AReceptors for the Development of Tolerance to the Sedative Action of Diazepam in Mice

Requirement of α₅-GABA_AReceptors for the Development of Tolerance to the Sedative Action of Diazepam in Mice