Lorazepam discontinuation promotes ‘inverse agonist’ effects of benzodiazepines

Schatzki, Andrew; Lopez, Fred; Greenblatt, David J.; Shader, Richard I.; Miller, Lawrence G.

doi:10.1111/j.1476-5381.1989.tb12617.x

Cited by 22 publications

(11 citation statements)

References 19 publications

(19 reference statements)

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“…The effects of benzodiazepine discontinua tion include sleep disturbances, recurrence of anxiety, and rarely seizures [1], all of which can also be associated with excitatory neuro transmission [17], Animal models of benzodi azepine discontinuation are characterized by increased locomotor activity and reduced sei zure threshold, again consistent with excitatory-mediated events [3], Such effects have also been noted to be consistent with the 'inverse agonist' class of benzodiazepines [ 13,22], Given the extensive regional overlap of glutamate and GABAa receptor ionophores in the brain [23,24], it is not surprising that interactions between the two receptor families exist. Several studies indicate that glutamate agonists, and NMDA in particular, promote GABA release in a number of brain regions [12, 17.…”

Section: Discussionmentioning

confidence: 92%

“…Control mice received vehicle alone. The dose of LRZ was selected based on prior studies from our laboratory [6,13]. A related study of CPP infusion [14] used a dose of 24 mg/kg/day which in studies of convulsant and anticonvulsant effects of NMDA agonists and antagonists, respectively, was shown to be higher than the ED50 [15][16][17], We selected a dose to be infused which was below its reported ED50 on these behavioral tests.…”

Section: Methodsmentioning

confidence: 99%

“…PTZ seizures were induced as previously described [ 13,20]. Briefly, tail veins were cannulatcd with a 25-gauge needle, and PTZ (7.5 mg/ml) was infused at a rate of 0.6 ml/min.…”

Section: Outcome Measuresmentioning

confidence: 99%

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The NMDA Receptor Competitive Antagonist CPP Modulates Benzodiazepine Tolerance and Discontinuation

Koff¹,

Pritchard²,

Greenblatt³

et al. 1997

Pharmacology

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Benzodiazepine discontinuation is characterized by a syndrome of increased activity and reduced seizure threshold that is similar to effects mediated by the glutamatergic system. To elucidate the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuation, we administered lorazepam, the NMDA antagonist CPP, and the combination of these compounds either concomitantly or consecutively to mice via osmotic pumps and evaluated pentylenetetrazole-induced seizure threshold, open-field activity, and benzodiazepine receptor binding during and after chronic administration. Animals receiving lorazepam alone developed partial tolerance at 7 days and complete tolerance at 14 days to the anticonvulsant effects of lorazepam. This effect was partly attenuated by CPP coadministration with lorazepam. This combination produced only partial tolerance. A reduction in seizure threshold was observed 4 days after discontinuation of lorazepam alone. This effect was abolished by coadministration of CPP with lorazepam and by CPP administration during the withdrawal period. Benzodiazepine binding in most structures examined was significantly reduced at 14 days during chronic lorazepam administration (versus 1 day), and coadministration of CPP did not alter this decrement. After lorazepam discontinuation, binding was increased at 4 and 7 days versus chronically treated animals and versus vehicle within the cerebral cortex. This effect was abolished by coadministration of CPP as well as by CPP administration during the lorazepam withdrawal period. These data support the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuation.

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

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The NMDA Receptor Competitive Antagonist CPP Modulates Benzodiazepine Tolerance and Discontinuation

Koff¹,

Pritchard²,

Greenblatt³

et al. 1997

Pharmacology

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“…alone as previously reported (Schatzki et al 1989). Mice treated with both lorazepam and PKl1195 had a signibcantly higher seizure threshold compared to…”

Section: Pentylenetetrazole-induced Seizuresmentioning

confidence: 99%

“…As previously described (Schatzki et al 1989), unre strained mice were infused intravenously with a solu· tion of penytlenetetrazole, 7.5 mg/ml (5.43 mmol/mI), at 0.30 ml/min. Infusion was terminated at the onset of a tonic-clonic seizure as determined by two ob servers.…”

Section: Pentylenetetrazole-induced Seizuresmentioning

confidence: 99%

Chronic Benzodiazepine Administration XI Concurrent Administration of PK11195 Attenuates Lorazepam Discontinuation Effects

Byrnes

Miller

Perkins

et al. 1993

Neuropsychopharmacol

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Chronic Benzodiazepine Administration: From the Patient to the Gene

Miller

1991

The Journal of Clinical Pharma

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Chronic benzodiazepine administration is associated with the development of tolerance and dependence. To evaluate the cellular mechanisms for these phenomena the authors developed a mouse model of chronic benzodiazepine exposure. The benzodiazepine agonists lorazepam, alprazolam, and clonazepam produced tolerance in this system, which was associated in each case with benzodiazepine and GABAA receptor downregulation. After discontinuation, a syndrome that included increased motor activity and receptor upregulation occurred with each of these compounds. A benzodiazepine antagonist, flumazenil, and an inverse agonist, FG 7142, were associated with receptor upregulation and increased activity during chronic administration. In contrast, a partial agonist (Ro16-6028) did not produce tolerance or receptor changes. Similar results were obtained in a culture system for clonazepam, flumazenil, and FG 7142. The increase in receptor binding after lorazepam discontinuation may be due to enhanced receptor synthesis. Changes in gene expression for GABAA receptor subunits also occur with chronic lorazepam administration, and they follow alterations in binding.

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Lorazepam discontinuation promotes ‘inverse agonist’ effects of benzodiazepines

Cited by 22 publications

References 19 publications

The NMDA Receptor Competitive Antagonist CPP Modulates Benzodiazepine Tolerance and Discontinuation

The NMDA Receptor Competitive Antagonist CPP Modulates Benzodiazepine Tolerance and Discontinuation

Chronic Benzodiazepine Administration XI Concurrent Administration of PK11195 Attenuates Lorazepam Discontinuation Effects

Chronic Benzodiazepine Administration: From the Patient to the Gene

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