Differential expression of benzodiazepine anticonvulsant cross-tolerance according to time following flurazepam or diazepam treatment

doi:10.1016/0091-3057(94)00405-8

Pharmacology Biochemistry and Behavior

Volume 51, Issues 2–3, June–July 1995, Pages 363-368

https://doi.org/10.1016/0091-3057(94)00405-8 Get rights and content

Abstract

In previous studies in which the anti-pentylenetetrazol (PTZ) effect of benzodiazepines was used to measure tolerance, the results depended on the benzodiazepine used for chronic treatment as well as the benzodiazepine given acutely to test for tolerance. In this study, the time course of tolerance reversal was studied in rats given two treatments known to cause anticonvulsant tolerance, 1-week flurazepam (FZP), and 3-week diazepam (DZP). Neither treatment altered convulsive threshold for IV PTZ, but both treatments decreased the convulsive threshold for bicuculline. Withdrawing DZP, but not FZP, treatment resulted in a loss of body weight. Twelve hours after 1-week FZP treatment, all benzodiazepines were significantly less effective, showing tolerance. Forty-eight hours after the 1-week FZP treatment, tolerance was still observed with DZP, FZP, and zolpidem, but was no longer present with clonazepam or bretazenil. After the 3-week DZP treatment, rats were tolerant to all benzodiazepines tested at 12 h of withdrawal, but had lost tolerance to all the drugs except bretazenil by 48 h. The results suggest differences in the way these benzodiazepines interact with their receptors, allowing differential expression of tolerance, and that chronic DZP and FZP treatments affected interactions of the benzodiazepines with their receptors, but not in the same fashion.

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High doses of diazepam (10–20 mg/kg) were shown to reduce the volume of acute carrageenan-induced inflammatory paw edema in rats. This effect was not observed after adrenalectomy or long-term use of similar doses of diazepam. The present experiment was undertaken to analyze the effects of long-term (21 daily injections) treatment with diazepam (10 mg/kg) on both carrageenan-induced paw edema (CIPE) and corticosterone serum levels. For comparison, the effects of a single and acute 10 mg/kg dose of diazepam were also analyzed. Results showed that: 1- long-term diazepam treatment induced no changes in CIPE values and corticosterone serum levels; 2- acute diazepam treatment reduced CIPE values and increased corticosterone serum levels; 3- the plasmatic levels of diazepam measured 1 hour after the single treatment or 1 hour after the last dose of long-term diazepam administration were not different. These results indicate the development of tolerance to diazepam effects on both CIPE and corticosterone serum levels and suggest a relevant role for corticosterone on diazepam-induced inhibition of acute inflammation. Data were discussed in the light of peripheral benzodiazepine receptor site (PBR) activation within adrenal gland cells by diazepam, thereby increasing the serum levels of corticosterone and thus reducing CIPE. Possible actions of diazepam on HPA axis activity and/or on cytokine network were also discussed.
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Two days following one-week administration of the benzodiazepine, flurazepam (FZP), rats exhibit anticonvulsant tolerance in vivo, while reduced GABA_A receptor-mediated inhibition and enhanced EPSP amplitude are present in CA1 pyramidal neurons in vitro. AMPA receptor (AMPAR)-mediated synaptic transmission in FZP-treated rats was examined using electrophysiological techniques in in vitro hippocampal slices. In CA1 pyramidal neurons from FZP-treated rats, the miniature excitatory postsynaptic current (mEPSC) amplitude was significantly increased (33%) without change in frequency, rise time or decay time. Moreover, mEPSC amplitude was not elevated in dentate granule neurons following 1-week FZP treatment or in CA1 pyramidal neurons following acute desalkyl-FZP treatment. Regulation of AMPAR number was assessed by quantitative autoradiography with the AMPAR antagonist, [³H]Ro48-8587. Specific binding was significantly increased in stratum pyramidale of hippocampal areas CA1 and CA2 and in proximal dendritic fields of CA1 pyramidal neurons. Regulation of AMPAR subunit proteins was examined using immunological techniques. Neither abundance nor distribution of GluR1–3 subunit proteins was different in the CA1 region following FZP treatment. These findings suggest that enhanced AMPAR currents, mediated at least in part by increased AMPAR number, may contribute to BZ anticonvulsant tolerance. Furthermore, these studies suggest an interaction between GABAergic and glutamatergic systems in the CA1 region which may provide novel therapeutic strategies for restoring BZ effectiveness.
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Citation Excerpt :
In subconvulsive doses, chronic administration of PTZ induces kindling phenomena and modifies the GABAA/BDZ/PCT-BB receptor complex, suppressing GABAA, BDZ receptors and GABA-stimulated 36Cl− influx into cortical membrane preparations [29,40,49–52,55]. BDZ agonists manifest a marked anticonvulsive effect on clonic–tonic seizures in PTZ-kindled rats, with a marked dose-effect dependence [3,5,13,34,53,54]. Chronic subthreshold stimulation of some brain structures, or chronic subconvulsive doses of convulsants result in kindling which is maintained for a long time [18,29,42,67].
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Behavioral analysis indicates benzodiazepine-tolerance mediated by the benzodiazepine binding-site at the GABA<inf>A</inf>-receptor
2001, Progress in Neuro-Psychopharmacology and Biological Psychiatry
- 1.
  GABA_A-receptor induced changes in locomotion and anxiety-like behaviors were studied in rats using an open-field and an elevated plus-maze. Acute and chronic doses of the benzodiazepine diazepam without and in combination with the GABA uptake inhibitor SKF-89976A were investigated.
- 2.
  Fifty-six male rats of the strain PVG/OlaHsd (PVG; 180–200g body wt) were used to assess the influence of the benzodiazepine binding-site to the development of tolerance. Rats were divided into six groups: The first receiving saline (0.9%), the second and third diazepam (10.0 mg/kg) daily for 23 days with or without an acute challenge of 2.0 mg/kg diazepam. The fourth group received diazepam (10.0 mg/kg) daily and acutely SKF-89976A (15.0 mg/kg) plus diazepam and the fifth and sixth group received acute treatment with diazepam (2.0 mg/kg) or SKF-89976A (15.0 mg/kg).
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  Under chronic treatment with diazepam the animals became tolerant to acute doses of diazepam in activity and anxiety-related behaviors. Acute treatment with SKF-89976A increased exploration. Parameters expressing anxiolytic-like behaviors were increased, too, but not all of them significantly. In diazepam tolerant animals SKF-89976A produced anxiolytic-like behaviors
- 4.
  We conclude that the BZ- and not the GABA-binding site at the GABA_A-receptor is involved in the development of BZ-tolerance.
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Nevertheless, the functional circuits responsible for PTZ seizure expression retain their DZP sensitivity. The locus of PTZ’s convulsant effect is likely the GABAA receptor [40,45], and the classical BZ’s reliably increase the PTZ seizure threshold [33]. However, PTZ’s interaction with other membrane proteins may also play a role in its convulsant effect [9], allowing the possibility that cocaine-induced changes in the interaction of BZ’s with the GABAA receptor could be masked.
Benzodiazepines are used to treat the anxiety associated with cocaine withdrawal, as well as cocaine-induced seizures. Since cocaine exposure was shown to affect BZ binding density, abuse liability, subjective hypnotic actions and seizure susceptibility, we assessed whether chronic cocaine alters diazepam’s anxiolytic and anticonvulsant actions. Changes in GABA_A receptor subunit protein expression were also assessed as they may relate to BZ activity at the receptor. Male Sprague–Dawley rats were injected with cocaine-HCl (15 mg/kg, i.p.) or saline once daily for 14 days. One day after the last injection, DZP (1 mg/kg i.p.) significantly increased time spent on and entries into open arms of an elevated plus maze in both saline- and cocaine-treated groups, yet the effect was greater in cocaine-treated rats. Eight days after cessation of treatment DZP did not have a significant anxiolytic effect in either group. To assess the effect of cocaine on DZP’s anticonvulsant actions, PTZ was infused at a constant rate via the lateral tail vein and clonus onset was recorded in the presence and absence of DZP (5 mg/kg, i.p). DZP significantly elevated seizure threshold in both groups of rats. Chronic cocaine also had no effect on the β-CCM seizure threshold. Quantitative immunohistochemistry of GABA_A receptor subunit protein demonstrated significant regulation of α2 (−10%) and β3 (+9%) subunits in the hippocampal dentate gyrus and CA1 regions, respectively. Small changes in GABAR subunit expression in specific brain areas may relate to DZP’s enhanced anxiolytic effectiveness whereas it’s anticonvulsant actions likely remain intact following cocaine administration.

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ArticleDifferential expression of benzodiazepine anticonvulsant cross-tolerance according to time following flurazepam or diazepam treatment

Abstract

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Neurosci. Lett.

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Article
Differential expression of benzodiazepine anticonvulsant cross-tolerance according to time following flurazepam or diazepam treatment