Reversible Modification of GABAA Receptor Subunit mRNA Expression During Tolerance to Diazepam-induced Cognition Dysfunction

doi:10.1016/S0028-3908(96)00071-8

Neuropharmacology

Volume 35, Issues 9–10, 1996, Pages 1465-1473

https://doi.org/10.1016/S0028-3908(96)00071-8 Get rights and content

Abstract

Benzodiazepines (BZs) that are endowed with full positive allosteric modulatory (FAM) activity on GABA_A receptors cause anterograde amnesia in both animals and humans. In rats subjected to a delayed object recognition test, diazepam, endowed with FAM activity, exerted an amnesic action, whereas BZs endowed with partial allosteric modulatory (PAM) activity on GABA_A receptors, such as imidazenil, failed to induce amnesia, even if administered at doses five times higher than those equipotent to a standard anticonvulsant dose of diazepam (17.6 μmol/kg/os). After discontinuation of 14 days' treatment with vehicle, diazepam, or imidazenil (three times daily with increasing doses starting from 17.6 μmol/kg/os for diazepam and 2.5 μmol/kg/os for imidazenil), we compared the persistence of tolerance to the amnesic effect of diazepam with the persistence of the changes in the content of four (α₁, α₅, γ_2L, γ_2S) GABA_A receptor subunit mRNAs in the fronto-parietal motor (FrPaM) cortex and the hippocampus. Rats receiving the long-term treatment with diazepam developed a tolerance to the amnesic effect of this drug and showed a decrease (30–50%) in the expression of mRNAs encoding for α₁, γ_2L, γ_2S GABA_A receptor subunits, an increase, by approximately 30%, of the expression of mRNA of the α₅ subunit in the FrPaM cortex and a decrease, by approximately 25%, in the expression of mRNA, of the α₁ subunit in the hippocampus. These changes of subunit mRNA expression and the tolerance to the amnesic effect of diazepam returned to control values 72 hr after termination of the long-term treatment with diazepam. No tolerance to the amnesic effect of diazepam and no changes in GABA_A receptor subunit mRNA expression were found in rats undergoing long-term treatment with imidazenil. Copyright © 1996 Elsevier Science Ltd

Section snippets

Animals

Male Sprague-Dawley rats weighing 250–275 g were housed three per cage and maintained on a 12-hr light/dark cycle (light from 7.00 a.m. to 7.00 p.m., dark from 7.00 p.m. to 7.00 a.m.). All the experimental animal procedures were carried out in strict accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Care and Use of Laboratory Animals Committee.

Materials

Diazepam and imidazenil were obtained from Hoffman-La Roche, Nutley, NJ.

Duration of tolerance to the diazepam-induced cognitive impairment

A standard dose of diazepam (17.6 μmol/kg/os) administered to naïve or vehicle-treated rats produced a cognitive impairment (see Methods for a description of the object recognition preference index; Table 1). This change was not associated with reduced locomotor activity or sedation, as demonstrated by motor activity measurements (motility scores for 3 min: vehicle 348 ± 60; diazepam 459 ± 22; each value is the mean ± SEM of six animals), or with changes in the duration of object exploration

DISCUSSION

Using the preference index of the object recognition test, we found that non-sedative anticonvulsant doses of diazepam administered orally to rats alter their short-term memory. In contrast, imidazenil, in anticonvulsant doses of up to five times higher than those equipotent to diazepam in both rats (see Results) and monkeys (Auta et al., 1995; Thompson et al., 1995), fails to change the results of a test for cognition. In order to evaluate the tolerance liability of the cognition impairment

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Reversible Modification of GABAA Receptor Subunit mRNA Expression During Tolerance to Diazepam-induced Cognition Dysfunction

Abstract

Section snippets

Animals

Materials

Duration of tolerance to the diazepam-induced cognitive impairment

DISCUSSION

Neuroscience

Eur. J. Pharmac.

Behav. Brain Res.

Behav. Brain Res.

Neurosci. Biobehav. Rev.

Eur. J. Pharmacol.

Trends Pharmac. Sci.

Trends Pharmacol. Sci.

Mol. Brain Res.

Anal. Biochem.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neurosci. Biobehav. Rev.

Dev. Brain Res.

Comparison of the effects of full and partial allosteric modulators of GABAA receptors on complex behavioral processes in monkeys

Behav. Pharmac.

Imidazenil, a partial positive allosteric modulator of GABAA receptors, exhibits low tolerance and dependence liabilities in the rat

J. Pharmacol. Exp. Ther.

Distinct developmental patterns of expression of rat α1, α5, γ2S and γ2L γ-aminobutyric acidA receptor subunit mRNAs in vivo and in vitro

J. Neurochem.

Expression patterns of γ-aminobutyric acid type A receptor subunit mRNAs in primary cultures of granule neurons and astrocytes from neonatal rat cerebella

Proc. Natn. Acad. Sci. U.S.A.

Physiological properties of anatomically identified axo-axonic cells in the rat hippocampus

J. Neurophysiol.

Double-immunolabeling analysis of GABAA receptor subunits in label-fracture replicas of cultured rat cerebellar granule cells

Receptors and Channels

Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease

Biochemistry

Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons

Nature

Time course for development of anticonvulsant tolerance and GABAergic subsensitivity after chronic diazepam

Brain Res.

Imidazenil: a potent benzodiazepine partial positive modulator of GABAergic transmission virtually devoid of tolerance liability

CNS Drug Rev.

Chronic benzodiazepine treatment decreases postsynaptic GABA sensitivity

Nature

Dose-response analysis of behavioral effects of diazepam: I. Learning and memory

Psychopharmacology

Reversible Modification of GABA_A Receptor Subunit mRNA Expression During Tolerance to Diazepam-induced Cognition Dysfunction

Comparison of the effects of full and partial allosteric modulators of GABA_A receptors on complex behavioral processes in monkeys

Imidazenil, a partial positive allosteric modulator of GABA_A receptors, exhibits low tolerance and dependence liabilities in the rat

Distinct developmental patterns of expression of rat α₁, α₅, γ_2S and γ_2L γ-aminobutyric acid_A receptor subunit mRNAs in vivo and in vitro

Double-immunolabeling analysis of GABA_A receptor subunits in label-fracture replicas of cultured rat cerebellar granule cells