Increase in expression of the GABAA receptor α4 subunit gene induced by withdrawal of, but not by long-term treatment with, benzodiazepine full or partial agonists

Follesa, Paolo; Cagetti, Elisabetta; Mancuso, Luisa; Biggio, Francesca; Manca, A; Maciocco, Elisabetta; Massa, Federico; Desole, Maria Speranza; Carta, Mario; Busonero, Fabio; Sanna, Enrico; Biggio, Giovanni

doi:10.1016/s0169-328x(01)00164-4

Cited by 52 publications

(64 citation statements)

References 41 publications

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“…Increases in a4 subunit protein were implicated in withdrawal from ethanol (Matthews et al, 1998;Sanna et al, 2003) and BZs (Follesa et al, 2001), while neurosteroid treatment was associated with withdrawal-anxiety, upregulation of GABAR a4 subunits and a reduction in mIPSC decay (Smith, 2002). Although a4 subunit protein was upregulated immediately after 1-week FZP treatment (Chen et al, 2000), mIPSC decay was unaltered on days 1 and 2 of withdrawal (Table 2; Zeng and Tietz, 1999).…”

Section: Discussionmentioning

confidence: 99%

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

Sickle

Kong

Tietz

2004

Neuropsychopharmacol

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Withdrawal from 1-week oral administration of the benzodiazepine (BZ), flurazepam (FZP) is associated with enhanced AMPA receptor (AMPAR)-mediated and reduced NMDA receptor (NMDAR)-mediated excitation in CA1 pyramidal neurons 2-days after cessation of FZP administration. The present study examined temporal regulation of glutamate receptor-mediated whole-cell currents in CA1 neurons from hippocampal slices prepared from 0-, 1-, 2-, and 4-day FZP-withdrawn rats in relation to expression of anxiety-like behavior during BZ withdrawal. AMPAR-mediated miniature excitatory postsynaptic current (mEPSC) amplitude was significantly increased in CA1 neurons from 1-and 2-day FZP-withdrawn rats, while evoked NMDAR EPSC amplitude was reduced only in neurons from 2-day FZP-withdrawn rats. Withdrawal-anxiety, measured in the elevated plus-maze, was observed 1 day, but not 0, 2, or 4 days, after FZP treatment with 1-day withdrawn rats spending significantly reduced time in open arms compared to controls. CA1 neuron hyperexcitability was evident from the significant increase in the frequency of extracellular, 4-AP-induced spike discharges in slices from 1-day FZP-withdrawn rats. Systemic injection of the NMDAR antagonist MK-801 (0.25 mg/kg) on day 1 of withdrawal prevented reduced NMDAR-mediated currents in CA1 neurons from 2-day FZP-withdrawn rats, whereas AMPAR-mediated currents remained upregulated. Furthermore, MK-801 'unmasked' withdrawal-anxiety in the same 2-day FZP-withdrawn rats. Systemic injection of the AMPAR antagonist GYKI-52466 (0.5 mg/kg) at the onset of withdrawal blocked increased AMPAR-mediated currents and withdrawal-anxiety in 1-day FZP-withdrawn rats. These findings suggest that increased CA1 neuron AMPAR-mediated excitation may contribute to hippocampal hyperexcitability and expression of withdrawal-anxiety after prolonged BZ exposure via NMDAR-mediated neural circuits.

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Section: Discussionmentioning

confidence: 99%

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

Sickle

Kong

Tietz

2004

Neuropsychopharmacol

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“…Indeed, chronic 7-or 14-day treatment with the BDZ diazepam or the α1-selective zolpidem increases α4 mRNA expression in rat cortex (Holt et al, 1996), in association with decreases in α1 expression. Other studies have indicated that withdrawal from chronic treatment with either diazepam or zolpidem also increases α4 mRNA expression in cultured cerebellar neurons (Holt et al, 1997;Follesa et al, 2001Follesa et al, , 2002.…”

Section: Benzodiazepinesmentioning

confidence: 96%

Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

Smith

Shen

Gong

et al. 2007

Pharmacology & Therapeutics

217

197

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Neurosteroids, such as the progesterone metabolite 3α-OH-5α[β]-pregnan-20-one (THP or [allo] pregnanolone), function as potent positive modulators of the GABA A receptor (GABAR) when acutely administered. However, fluctuations in the circulating levels of this steroid at puberty, across endogenous ovarian cycles, during pregnancy or following chronic stress produce periods of prolonged exposure and withdrawal, where changes in GABAR subunit composition may occur as compensatory responses to sustained levels of inhibition. A number of laboratories have demonstrated that both chronic administration of THP as well as its withdrawal transiently increase expression of the α4 subunit of the GABAR in several areas of the central nervous system (CNS) as well as in in vitro neuronal systems. Receptors containing this subunit are insensitive to benzodiazepine (BDZ) modulation and display faster deactivation kinetics, which studies suggest underlie hyperexcitability states. Similar increases in α4 expression are triggered by withdrawal from other GABA-modulatory compounds, such as ethanol and BDZ, suggesting a common mechanism. Other studies have reported puberty or estrous cycle-associated increases in δ-GABAR, the most sensitive target of these steroids which underlies a tonic inhibitory current. In the studies reported here, the effect of steroids on inhibition, which influence anxiety state and seizure susceptibility, depend not only on the subunit composition of the receptor but also on the direction of Cl -current generated by these target receptors. The effect of neurosteroids on GABAR function thus results in behavioral outcomes relevant for pubertal mood swings, premenstrual dysphoric disorder and catamenial epilepsy, which are due to fluctuations in endogenous steroids.

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“…Treatment of cultured rat CGCs with diazepam reduced ␣1 mRNA expression slightly (Follesa et al, 2001a(Follesa et al, , 2002, but treatments with imidazenil, zaleplon, or zolpidem were ineffective (Table 8). Withdrawal (6 h) of CGCs from diazepam, imidazenil, zaleplon, and zolpidem decreased ␣1 mRNA by 20 to 37% (Table 9).…”

Section: A Benzodiazepinesmentioning

confidence: 99%

Regulation of GABA_AReceptor Subunit Expression by Pharmacological Agents

2010

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Increase in expression of the GABAA receptor α4 subunit gene induced by withdrawal of, but not by long-term treatment with, benzodiazepine full or partial agonists

Cited by 52 publications

References 41 publications

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

Regulation of GABA_AReceptor Subunit Expression by Pharmacological Agents

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Increase in expression of the GABAA receptor α4 subunit gene induced by withdrawal of, but not by long-term treatment with, benzodiazepine full or partial agonists

Cited by 52 publications

References 41 publications

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

Regulation of GABAAReceptor Subunit Expression by Pharmacological Agents

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Regulation of GABA_AReceptor Subunit Expression by Pharmacological Agents