Bi-directional changes in the levels of messenger RNAs encoding γ-aminobutyric acidA receptor α subunits after flurazepam treatment

doi:10.1016/0922-4106(92)90051-V

European Journal of Pharmacology: Molecular Pharmacology

Volume 226, Issue 4, 3 August 1992, Pages 335-341

https://doi.org/10.1016/0922-4106(92)90051-V Get rights and content

Abstract

Changes in γ-aminobutyric acid_A (GABA_A) receptor function have been observed following chronic benzodiazepine administration. The molecular mechanisms responsible are unknown, but one possibility is that benzodiazepines induce alterations in the expression of genes which encode subunits of the GABA_A receptor complex, resulting in changes in the receptor structure and function. We have investigated this hypothesis by evaluating the effect of flurazepam 40 mg/kg i.p. on brain levels of the mRNAs which encode the α1, α2, α3, α5, and α6 subunits of the GABA_A receptor complex. Rats were treated with flurazepam or vehicle for up to 32 days. No changes were found in the levels of α1 and α2 mRNA. A rapid decrease was found in the level of α5 mRNA; α3 mRNA was increased by 4 days of treatment and this was followed by an increase in α6 levels. These results support the hypothesis that the alteration in GABA_A receptor function after benzodiazepine administration results from changes in subunit gene expression. Furthermore, the predicted consequences of the pattern of mRNA changes we have observed suggest that altered gene expression may be important in the genesis of benzodiazepine tolerance.

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However, as already described, Holt and colleagues (1999) presented evidence that there was no temporal relationship between changes in expression of particular GABAA receptor subunit mRNAs and allosteric uncoupling. There has also been a lot of controversy in the reported effects of chronic BZ treatment on the expression of GABAA receptor subunit genes, with reports of increased, reduced, or unchanged expression of particular subunits (Heninger et al., 1990; Holt et al., 1996; Impagnatiello et al., 1996; Kang & Miller, 1991; O'Donovan et al., 1992a, 1992b; Pratt et al., 1998; Tietz et al., 1993; Zhao et al., 1994). Pratt and colleagues (1998) have provided evidence from in situ hybridisation studies that changes in α1, α4, or γ2 GABAA receptor subunit gene expression are generally not accompanied by changes in neural activity in the particular brain structures revealed by their previous 2-deoxyglucose autoradiography studies (Brett & Pratt, 1995; Laurie & Pratt, 1989, 1993) during DZP tolerance and withdrawal from low-dose i.p. DZP treatment.
Knowledge of the neural mechanisms underlying the development of benzodiazepine (BZ) dependence remains incomplete. The γ-aminobutyric acid (GABA_A) receptor, being the main locus of BZ action, has been the main focus to date in studies performed to elucidate the neuroadaptive processes underlying BZ tolerance and withdrawal in preclinical studies. Despite this intensive effort, however, no clear consensus has been reached on the exact contribution of neuroadaptive processes at the level of the GABA_A receptor to the development of BZ tolerance and withdrawal. It is likely that changes at the level of this receptor are inadequate in themselves as an explanation of these neuroadaptive processes and that neuroadaptations in other receptor systems are important in the development of BZ dependence. In particular, it has been hypothesised that as part of compensatory mechanisms to diazepam-induced chronic enhancement of GABAergic inhibition, excitatory mechanisms (including the glutamatergic system) become more sensitive [Behav. Pharmacol. 6 (1995) 425], conceivably contributing to BZ tolerance development and/or expression of withdrawal symptoms on cessation of treatment, including increased anxiety and seizure activity. Glutamate is a key candidate for changes in excitatory transmission mechanisms and BZ dependence, (1) since there are defined neuroanatomical relationships between glutamatergic and GABAergic neurons in the CNS and (2) because of the pivotal role of glutamatergic neurotransmission in mediating many forms of synaptic plasticity in the CNS, such as long-term potentiation and kindling events. Thus, it is highly possible that glutamatergic processes are also involved in the neuroadaptive processes in drug dependence, which can conceivably be considered as a form of synaptic plasticity. This review provides an overview of studies investigating changes in the GABAergic and glutamatergic systems in the brain associated with BZ dependence, with particular attention to the possible differential involvement of N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors in these processes.
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Bi-directional changes in the levels of messenger RNAs encoding γ-aminobutyric acidA receptor α subunits after flurazepam treatment

Abstract

Neurosci. Lett.

FEBS Lett.

Brain Res.

Brain Res. Bull.

Neuron

Neuron

Neuropharmacology

FEBS Lett.

Eur. J. Pharmacol.

J. Biol. Chem.

Life Sci.

Eur. J. Pharmacol.

Neuron

Brain Res.

Neurosci. Lett.

FEBS Lett.

γ-Aminobutyric acidA receptor heterogeneity is increased by alternative splicing of a novel β-subunit gene transcript

J. Neurochem.

Evidence for involvement of GABA in the action of benzodiazepines: studies on rat cerebellum

Adv. Biochem. Pharmacol.

Molecular biology of mammalian amino acid receptors

FASEB J.

Chronic benzodiazepine treatment decreases postsynaptic GABA sensitivity

Nature

Chronic benzodiazepine agonist exposure and its consequences to GABA-benzodiazepine interactions

Bi-directional changes in the levels of messenger RNAs encoding γ-aminobutyric acid_A receptor α subunits after flurazepam treatment

γ-Aminobutyric acid_A receptor heterogeneity is increased by alternative splicing of a novel β-subunit gene transcript