The cerebellar GABAA α6 subunit is differentially modulated by chronic ethanol exposure in normal (R100R) and mutated (Q100Q) sNP rats

Sanna, Angela; Congeddu, Elena; Saba, Luisella; Porcella, Anna; Marchese, Giorgio; Ruiu, Stefania; Casti, Paola; Saba, Pierluigi; Pani, Luca

doi:10.1016/j.brainres.2003.11.013

Cited by 9 publications

(7 citation statements)

References 38 publications

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“…Neuronal cell cultures, as well as animal models, show changes in mRNA levels for different GABA A R subunits after alcohol exposure (Kumar et al, 2004 ; Wafford, 2005 ). For example, alterations in GABA A R subunit expression levels, including changes in the levels of extra-synaptic subunits α6 and δ, have been detected in the cerebellum of rats chronically treated with ethanol (Mhatre and Ticku, 1992 ; Morrow et al, 1992 ; Vekovischeva et al, 2000 ; Sanna et al, 2004 ; Marutha Ravindran et al, 2007 ). In neonatal rats, repetitive exposure to ethanol increased expression of the δ subunit in cerebellar granule cells, but the properties of neither tonic nor phasic GABAergic currents were modified (Diaz et al, 2014 ).…”

Section: Effects Of Chronic Ethanol Exposure On the Gabaergic Systemmentioning

confidence: 99%

Potentiation of Gamma Aminobutyric Acid Receptors (GABAAR) by Ethanol: How Are Inhibitory Receptors Affected?

Förstera

Castro

Moraga-Cid

et al. 2016

Front. Cell. Neurosci.

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In recent years there has been an increase in the understanding of ethanol actions on the type A γ-aminobutyric acid chloride channel (GABAAR), a member of the pentameric ligand gated ion channels (pLGICs). However, the mechanism by which ethanol potentiates the complex is still not fully understood and a number of publications have shown contradictory results. Thus many questions still remain unresolved requiring further studies for a better comprehension of this effect. The present review concentrates on the involvement of GABAAR in the acute actions of ethanol and specifically focuses on the immediate, direct or indirect, synaptic and extra-synaptic modulatory effects. To elaborate on the immediate, direct modulation of GABAAR by acute ethanol exposure, electrophysiological studies investigating the importance of different subunits, and data from receptor mutants will be examined. We will also discuss the nature of the putative binding sites for ethanol based on structural data obtained from other members of the pLGICs family. Finally, we will briefly highlight the glycine gated chloride channel (GlyR), another member of the pLGIC family, as a suitable target for the development of new pharmacological tools.

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Section: Effects Of Chronic Ethanol Exposure On the Gabaergic Systemmentioning

confidence: 99%

Potentiation of Gamma Aminobutyric Acid Receptors (GABAAR) by Ethanol: How Are Inhibitory Receptors Affected?

Förstera

Castro

Moraga-Cid

et al. 2016

Front. Cell. Neurosci.

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“…Interestingly, Sardinian alcohol non‐preferring rats, selected for their low alcohol preference and consumption, carry a point mutation ( R100Q ) in the gene coding for the GABA A receptor α6 subunit. Rats carrying this mutation voluntarily drank less alcohol than did normal rats during the acquisition phase, but this difference was lost during the maintenance phase ( Sanna et al ., 2004 ). However, in a recent study by Botta et al .…”

Section: Initiation Of Alcohol Consumptionmentioning

confidence: 99%

Neuropharmacology of alcohol addiction

Vengeliene

Bilbao

Molander

et al. 2008

British J Pharmacology

498

389

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Despite the generally held view that alcohol is an unspecific pharmacological agent, recent molecular pharmacology studies demonstrated that alcohol has only a few known primary targets. These are the NMDA, GABA A , glycine, 5-hydroxytryptamine 3 (serotonin) and nicotinic ACh receptors as well as L-type Ca 2 þ channels and G-protein-activated inwardly rectifying K þ channels. Following this first hit of alcohol on specific targets in the brain, a second wave of indirect effects on a variety of neurotransmitter/neuropeptide systems is initiated that leads subsequently to the typical acute behavioural effects of alcohol, ranging from disinhibition to sedation and even hypnosis, with increasing concentrations of alcohol. Besides these acute pharmacodynamic aspects of alcohol, we discuss the neurochemical substrates that are involved in the initiation and maintenance phase of an alcohol drinking behaviour. Finally, addictive behaviour towards alcohol as measured by alcoholseeking and relapse behaviour is reviewed in the context of specific neurotransmitter/neuropeptide systems and their signalling pathways. The activity of the mesolimbic dopaminergic system plays a crucial role during the initiation phase of alcohol consumption. Following long-term, chronic alcohol consumption virtually all brain neurotransmission seems to be affected, making it difficult to define which of the systems contributes the most to the transition from controlled to compulsive alcohol use. However, compulsive alcohol drinking is characterized by a decrease in the function of the reward neurocircuitry and a recruitment of antireward/stress mechanisms comes into place, with a hypertrophic corticotropin-releasing factor system and a hyperfunctional glutamatergic system being the most important ones.

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“…Polymorphisms in the rat Gabra6 regulatory region as well as in the Gabra1, Gabrb2, and Gabrg2 genes have been found to be linked to the Q allele of Gabra6 (Congeddu et al, 2003;Saba et al, 2005). It is not known if these polymorphisms have any effect on interactions between GABA A -Rs and EtOH, although it has been postulated that the Gabra6 regulatory region mutations influence α 6 expression, especially during the course of chronic EtOH administration (Saba et al, 2005;Sanna et al, 2004). The QTL mapping results further suggest that these or any other linked polymorphisms, if actually present in the ANT rats, do not contribute to the EtOH sensitivity difference between the AT and ANT phenotypes.…”

Section: Qtl Mapping Studies Related To α 6 -R100q In the At And Ant mentioning

confidence: 99%

Modulation of GABAA receptors in cerebellar granule neurons by ethanol: a review of genetic and electrophysiological studies

Botta

Radcliffe

Carta

et al. 2007

Alcohol

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Cerebellar granule neurons (CGNs) receive inhibitory input from Golgi cells in the form of phasic and tonic currents that are mediated by postsynaptic and extrasynaptic gamma-aminobutyric acid type A (GABAA) receptors, respectively. Extrasynaptic receptors are thought to contain alpha6betaxdelta subunits. Here, we review studies on ethanol (EtOH) modulation of these receptors, which have yielded contradictory results. Although studies with recombinant receptors expressed in Xenopus oocytes indicate that alpha6beta3delta receptors are potently enhanced by acute exposure to low (>or=3 mM) EtOH concentrations, this effect was not observed when these receptors were expressed in Chinese hamster ovary cells. Slice recordings of CGNs have consistently shown that EtOH increases the frequency of phasic spontaneous inhibitory postsynaptic currents (sIPSCs), as well as the tonic current amplitude and noise. However, there is a lack of consensus as to whether EtOH directly acts on extrasynaptic receptors or modulates them indirectly; that is, via an increase in spillover of synaptically released GABA. It was recently demonstrated that an R to Q mutation of amino acid 100 of the alpha6 subunit increases the effect of EtOH on both sIPSCs and tonic current. These electrophysiological findings have not been reproducible in our hands. Moreover, it was shown the alpha6-R100Q mutation enhances sensitivity to the motor-impairing effects of EtOH in outbred Sprague-Dawley rats, but this was not observed in a line of rats selectively bred for high sensitivity to EtOH-induced motor alterations (Alcohol Non-Tolerant rats). We conclude that currently there is insufficient evidence conclusively supporting a direct potentiation of extrasynaptic GABAA receptors following acute EtOH exposure in CGNs.

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The cerebellar GABAA α6 subunit is differentially modulated by chronic ethanol exposure in normal (R100R) and mutated (Q100Q) sNP rats

Cited by 9 publications

References 38 publications

Potentiation of Gamma Aminobutyric Acid Receptors (GABAAR) by Ethanol: How Are Inhibitory Receptors Affected?

Potentiation of Gamma Aminobutyric Acid Receptors (GABAAR) by Ethanol: How Are Inhibitory Receptors Affected?

Neuropharmacology of alcohol addiction

Modulation of GABAA receptors in cerebellar granule neurons by ethanol: a review of genetic and electrophysiological studies

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