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Neurosteroids, GABAA receptors, and ethanol dependence

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Abstract

Rationale

Changes in the expression of type A receptors for γ-aminobutyric acid (GABA) represent one of the mechanisms implicated in the development of tolerance to and dependence on ethanol. The impact of such changes on the function and pharmacological sensitivity of GABAA receptors (GABAARs) has remained unclear, however. Certain behavioral and electrophysiological actions of ethanol are mediated by an increase in the concentration of neuroactive steroids in the brain that results from stimulation of the hypothalamic–pituitary–adrenal (HPA) axis. Such steroids include potent modulators of GABAAR function.

Objectives

We have investigated the effect of ethanol exposure and withdrawal on subunit expression and receptor function evaluated by subunit selective compounds, as well as the effects of short-term exposure to ethanol on both neurosteroid synthesis and GABAAR function, in isolated neurons and brain tissue.

Results

Chronic treatment with and subsequent withdrawal from ethanol alter the expression of genes for specific GABAAR subunits in cultured rat neurons, and these changes are associated with alterations in receptor function and pharmacological sensitivity to neurosteroids, zaleplon, and flumazenil. Acute ethanol exposure increases the amount of 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) in hippocampal slices by a local action independent of the activity of the HPA axis. This effect of ethanol was associated with an increased amplitude of GABAAR-mediated miniature inhibitory postsynaptic currents recorded from CA1 pyramidal neurons in such slices.

Conclusions

Chronic ethanol exposure elicits changes in the subunit composition of GABAARs, which, in turn, likely contribute to changes in receptor function associated with the altered pharmacological and behavioral sensitivity characteristic of ethanol tolerance and dependence. Ethanol may also modulate GABAAR function by increasing the de novo synthesis of neurosteroids in the brain in a manner independent of the HPA axis. This latter mechanism may play an important role in the central effects of ethanol.

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Acknowledgements

This study is supported by grant CE00042735 (Project Center of Excellence for the Neurobiology of Dependence, D.M. 21 January 2001), FIRB grant RBNE0195AX, and PRIN grants 2002053959-001 and 2001055774 from the Ministry of Instruction, Universities, and Research, Italy; by NIAAA grant U01AA13641 from the Sardinian Health Ministry; and, in part, by GIO.I.A. Foundation (Pisa).

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  1. Department of Experimental Biology “Bernardo Loddo”, University of Cagliari, Cagliari, 09123, Italy

    Paolo Follesa, Francesca Biggio, Giuseppe Talani, Luca Murru, Mariangela Serra, Enrico Sanna & Giovanni Biggio

  2. Center of Excellence for the Neurobiology of Dependence, University of Cagliari, Cagliari, 09123, Italy

    Paolo Follesa, Francesca Biggio, Giuseppe Talani, Luca Murru, Mariangela Serra, Enrico Sanna & Giovanni Biggio

  3. CNR Institute of Neuroscience, Section of Neuropsychopharmacology, Cagliari, 09123, Italy

    Mariangela Serra & Giovanni Biggio

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  1. Paolo Follesa
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  2. Francesca Biggio
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  3. Giuseppe Talani
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Correspondence to Giovanni Biggio.

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Follesa, P., Biggio, F., Talani, G. et al. Neurosteroids, GABAA receptors, and ethanol dependence. Psychopharmacology 186, 267–280 (2006). https://doi.org/10.1007/s00213-005-0126-0

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  • DOI: https://doi.org/10.1007/s00213-005-0126-0

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