Chronic Intermittent Ethanol Regulates Hippocampal GABA(A) Receptor Delta Subunit Gene Expression

Follesa, Paolo; Floris, Gabriele; Asuni, Gino Paolo; Ibba, Antonio; Tocco, Maria Giuseppina; Zicca, Luca; Mercante, Beniamina; Deriu, Franca; Gorini, Giorgio

doi:10.3389/fncel.2015.00445

Cited by 14 publications

(12 citation statements)

References 79 publications

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“…Collectively, this work demonstrates the importance of δ subunit-containing GABA A receptors in the VTA of female mice during binge-like drinking. Further, the evidence of a role for δ subunit-containing GABA A receptors in alcohol consumption also has implications regarding withdrawal, in which changes in δ expression have been observed in the hippocampus 46 ; however, it remains to be determined whether alcohol exposure alters GABA A R δ subunit expression in brain regions implicated in alcohol intake, such as the VTA.…”

Section: Discussionmentioning

confidence: 99%

Female-specific decreases in alcohol binge-like drinking resulting from GABAA receptor delta-subunit knockdown in the VTA

Darnieder

Melón

et al. 2019

Sci Rep

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Binge drinking is short-term drinking that achieves blood alcohol levels of 0.08 g/dl or above. It exhibits well-established sex differences in GABAergic inhibitory neurotransmission, including extrasynaptic δ subunit-containing GABA A receptors (δ-GABA A Rs) that mediate tonic inhibition, or synaptic γ2-containing GABA A Rs which underlie fast, synaptic, phasic inhibition have been implicated in sex differences in binge drinking. Ovarian hormones regulate δ-GABA A Rs, further implicating these receptors in potential sex differences. Here, we explored the contribution of extrasynaptic δ-GABA A Rs to male and female binge-like drinking in a critical area of mesolimbic circuitry—the ventral tegmental area (VTA). Quantitative PCR revealed higher Gabrd transcript levels and larger tonic currents in the VTA of females compared to males. In contrast, male and female Gabrg 2 transcript levels and measures of phasic inhibition were equivalent. Intra-VTA infusion of AAV-Cre-GFP in floxed Gabrd mice downregulated δ-GABA A Rs and decreased binge-like drinking in females. There was no significant difference in either male or female mice after GABA A R γ2 subunit reduction in the VTA following AAV-Cre-GFP infusion in floxed Gabrg2 mice. Collectively, these findings suggest sex differences and GABA A R subunit specificity in alcohol intake.

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Section: Discussionmentioning

confidence: 99%

Female-specific decreases in alcohol binge-like drinking resulting from GABAA receptor delta-subunit knockdown in the VTA

Darnieder

Melón

et al. 2019

Sci Rep

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“…Thirteen weeks old mice were placed in a dedicated room with 12:12 inverted light/dark cycle and allowed to adapt to the new light/dark cycle for 1 week before the beginning of testing. We used a modified sucrose-fading procedure as we have previously described ( Sanna et al, 2011 ; Follesa et al, 2015 ). Briefly, the mice were provided with daily access to an alcohol solution for 2 h, beginning 30 min prior to the dark cycle start point.…”

Section: Methodsmentioning

confidence: 99%

“…Immediately after decapitation, blood samples (140 μl) were collected from the trunk with two heparinized capillary tubes, transferred to 1.5-ml test tubes containing 10 μl heparin, and mixed; 100 μl aliquots of blood was then subjected to BAC analysis by static headspace capillary gas chromatography/mass spectrometry following the same protocol that we previously described in Follesa et al (2015) . BAC values were expressed in mg/dl units.…”

Section: Methodsmentioning

confidence: 99%

“…From each sample, 1 μg of RNA was employed for single-strand cDNA synthesis using an i Script ™ cDNA synthesis kit (Bio-Rad, Hercules, CA, United States) according to the manufacturer’s instructions. Diluted cDNA (1:50) was used as a template for quantitative RT-PCR to determine GABA A R subunit mRNA levels using the same experimental protocol and thermocycler conditions we previously described in Follesa et al (2015) . The primer assay “QuantiTect” from Qiagen (Hilden, Germany) was used for measuring the following GABA A R subunits and housekeeping genes: GABA A R α4 (product number 249900, NM_010251, final conc.…”

Section: Methodsmentioning

confidence: 99%

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Increased Voluntary Alcohol Consumption in Mice Lacking GABAB(1) Is Associated With Functional Changes in Hippocampal GABAA Receptors

Floris

Asuni

Talani

et al. 2022

Front. Behav. Neurosci.

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Gamma-aminobutyric acid type B receptor (GABABR) has been extensively involved in alcohol use disorders; however, the mechanisms by which this receptor modulates alcohol drinking behavior remain murky. In this study, we investigate alcohol consumption and preference in mice lacking functional GABABR using the 2-bottle choice paradigm. We found that GABAB(1), knockout (KO), and heterozygous (HZ) mice drank higher amounts of an alcoholic solution, preferred alcohol to water, and reached higher blood alcohol concentrations (BACs) compared to wild-type (WT) littermates. The GABABR agonist GHB significantly reduced alcohol consumption in the GABAB(1) HZ and WT but not in the KO mice. Next, because of a functional crosstalk between GABABR and δ-containing GABAA receptor (δ-GABAAR), we profiled δ subunit mRNA expression levels in brain regions in which the crosstalk was characterized. We found a loss of the alcohol-sensitive GABAAR δ subunit in the hippocampus of the GABAB(1) KO alcohol-naïve mice that was associated with increased ɣ2 subunit abundance. Electrophysiological recordings revealed that these molecular changes were associated with increased phasic inhibition, suggesting a potential gain of synaptic GABAAR responsiveness to alcohol that has been previously described in an animal model of excessive alcohol drinking. Interestingly, voluntary alcohol consumption did not revert the dramatic loss of hippocampal δ-GABAAR occurring in the GABAB(1) KO mice but rather exacerbated this condition. Finally, we profiled hippocampal neuroactive steroids levels following acute alcohols administration in the GABAB(1) KO and WT mice because of previous involvement of GABABR in the regulation of cerebral levels of these compounds. We found that systemic administration of alcohol (1.5 g/kg) did not produce alcohol-induced neurosteroid response in the GABAB(1) KO mice but elicited an expected increase in the hippocampal level of progesterone and 3α,5α-THP in the WT controls. In conclusion, we show that genetic ablation of the GABAB(1) subunit results in increased alcohol consumption and preference that were associated with functional changes in hippocampal GABAAR, suggesting a potential mechanism by which preference for alcohol consumption is maintained in the GABAB(1) KO mice. In addition, we documented that GABAB(1) deficiency results in lack of alcohol-induced neurosteroids, and we discussed the potential implications of this finding in the context of alcohol drinking and dependence.

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“…Alcohol exposure can change the expression of GABAAR subunits (Liang et al, 2004;Olsen et al, 2012;Lindemeyer et al, 2014;Follesa et al, 2015) and sex differences in GABAAR δ subunit expression has been reported (Maguire et al, 2005). Given that changes in the expression of the GABAAR δ subunit, whether through genetic deletions or associated with hormone fluctuations during pregnancy, can alter oscillation frequencies in the hippocampus Mody, 2013, 2015), we hypothesized that altered expression of the GABAAR δ subunit, expressed on PV interneurons in the BLA, may contribute to our observed sex differences in BLA network states.…”

Section: Repeated Alcohol Exposure Alters δ Expression On Pv Interneurons In the Blamentioning

confidence: 99%

Sex differences in the alcohol-mediated modulation of BLA network states

DiLeo

Antonoudiou

et al. 2022

Preprint

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About 85% of adults in the United States report drinking alcohol in their lifetime. Mood disorders, like generalized anxiety disorder and major depression, are highly comorbid with alcohol use. The basolateral amygdala (BLA) is an area of the brain that is heavily implicated in both mood disorders and alcohol use disorder. Importantly, modulation of BLA network/oscillatory states via parvalbumin-positive (PV) GABAergic interneurons has been shown to control the behavioral expression of fear and anxiety. Further, PV interneurons express a high density of δ-subunit-containing GABAA receptors (GABAARs), which are sensitive to low concentrations of alcohol. Our lab previously demonstrated that δ-subunit-containing GABAARs on PV interneurons in the BLA influence voluntary ethanol intake and anxiety-like behavior in withdrawal. Therefore, we hypothesized that the effects of alcohol may modulate BLA network states that have been associated with fear and anxiety behaviors via δ-GABAARs on PV interneurons in the BLA. Given the impact of ovarian hormones on the expression of δ-GABAARs, we examined the ability of alcohol to modulate local field potentials (LFPs) in the BLA from male and female C57BL/6J and Gabrd-/- mice after acute and repeated exposure to alcohol. Here, we demonstrate that acute and repeated alcohol can differentially modulate oscillatory states in male and female C57BL/6J mice, a process which involves δ-GABAARs. This is the first study to demonstrate that alcohol is capable of altering network states implicated in both anxiety and alcohol use disorders.

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Chronic Intermittent Ethanol Regulates Hippocampal GABA(A) Receptor Delta Subunit Gene Expression

Cited by 14 publications

References 79 publications

Female-specific decreases in alcohol binge-like drinking resulting from GABAA receptor delta-subunit knockdown in the VTA

Female-specific decreases in alcohol binge-like drinking resulting from GABAA receptor delta-subunit knockdown in the VTA

Increased Voluntary Alcohol Consumption in Mice Lacking GABAB(1) Is Associated With Functional Changes in Hippocampal GABAA Receptors

Sex differences in the alcohol-mediated modulation of BLA network states

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