GABA-A and NMDA receptor subunit mRNA expression is altered in the caudate but not the putamen of the postmortem brains of alcoholics.

paper Cited Public

Authors: Bhandage, Amol K; Jin, Zhe; Bazov, Igor; Kononenko, Olga; Bakalkin, Georgy; Korpi, Esa R; Birnir, Bryndis
Year: 2014
Journal: Frontiers in cellular neuroscience
PMID: 25538565
DOI: 10.3389/fncel.2014.00415
PMCID: PMC4257153

Figure 1

Expression of ionotropic glutamate receptor subunit mRNAs in the caudate of control subjects (n = 29). The mRNA level of each subunit was normalized to reference gene ACTB and presented as mean ± SEM.

Figure 2

Expression of ionotropic glutamate receptor subunits mRNA in the caudate of controls (n = 29) and alcoholics (n = 29). Data from each group is presented as scatter dot plot (°) with mean and 95% confidence interval and box and whiskers plot with median and whiskers plotted by Tukey method to determine outliers (•, above or below the whiskers). Statistical analysis was performed by excluding outliers. One Way ANOVA with Bonferroni post-hoc test, GluA1, df = 49, p = 0.40; GluK2, df = 49, p = 0.16; GluK4, df = 49, p = 0.14; GluN2C, df = 49, p = 0.38. Kruskal–Wallis ANOVA on ranks with Dunn's post-hoc test, GluA2, H(1, 53) = 1.73, p = 0.19; GluA3, H(1, 54) = 0.3, p = 0.86; GluA4, H(1, 58) = 0.77, p = 0.38; GluK1, H(1, 55) = 2.79, p = 0.095; GluK3, H(1, 56) = 0.23, p = 0.63; GluK5, H(1, 56) = 2.37, p = 0.12; GluN1, H(1, 28) = 3.80, p = 0.051; GluN2A, H(1, 54) = 6.82, p = 0.009; GluN2B, H(1, 54) = 3.27, p = 0.07; GluN2D, H(1, 56) = 1.68, p = 0.20; GluN3A, H(1, 52) = 0.10, p = 0.75; GluD1, H(1, 55) = 9.7, p = 0.0018; GluD2, H(1, 50) = 10.75, p = 0.001. **p < 0.01, ***p < 0.001.

Figure 3

Expression of GABA-A channel subunit mRNAs in the caudate of control subjects (n = 29). The mRNA level of each subunit was normalized to reference gene ACTB and presented as mean ± SEM.

Figure 4

Expression of GABA-A channel subunits mRNA in the caudate of controls (n = 29) and alcoholics (n = 29). Data from each group is presented as scatter dot plot (°) with mean and 95% confidence interval and box and whiskers plot with median and whiskers plotted by Tukey method to determine outliers (•, above or below the whiskers). Statistical analysis was performed by excluding outliers. One Way ANOVA with Bonferroni post-hoc test, α1, df = 47, p = 0.83; α2, df = 47, p = 0.17; α4, df = 47, p = 0.33; β 1, df = 47, p = 0.42; β 2, df = 47, p = 0.57; β 3, df = 47, p = 0.81; δ, df = 47, p = 0.021; γ2, df = 47, p = 0.22; γ3, df = 47, p = 0.79. Kruskal–Wallis ANOVA on ranks with Dunn's post-hoc test, α3, H(1, 51) = 3.07, p = 0.08; α5, H(1, 56) = 0.86, p = 0.35; α6, H(1, 51) = 0.0072, p = 0.93; ε, H(1, 53) = 8.41, p = 0.0037; γ1, H(1, 53) = 5.94, p = 0.015; θ, H(1, 54) = 1.59, p = 0.19; ρ2, H(1, 55) = 23.68, p = 0.00001. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 5

Expression of ionotropic glutamate receptor subunit mRNAs in the putamen of control subjects (n = 29). The mRNA level of each subunit was normalized to reference gene ACTB and presented as mean ± SEM.

Figure 6

Expression of ionotropic glutamate receptor subunits mRNA in the putamen of controls (n = 29) and alcoholics (n = 29). Data from each group is presented as scatter dot plot (°) with mean and 95% confidence interval and box and whiskers plot with median and whiskers plotted by Tukey method to determine outliers (•, above or below the whiskers). Statistical analysis was performed by excluding outliers. Kruskal–Wallis ANOVA on ranks with Dunn's post-hoc test, GluA1, H(1, 56) = 0.34, p = 0.56; GluA2, H(1, 58) = 0.2, p = 0.66; GluA3, H(1, 57) = 0.03, p = 0.86; GluA4, H(1, 56) = 0.69, p = 0.41; GluK1, H(1, 56) = 0.38, p = 0.54; GluK2, H(1, 57) = 0.16, p = 0.69; GluK3, H(1, 54) = 0.0012, p = 0.97; GluK4, H(1, 53) = 0.0079, p = 0.93; GluK5, H(1, 57) = 0.0041, p = 0.95; GluN1, H(1, 57) = 0.66, p = 0.42; GluN2A, H(1, 53) = 1.22, p = 0.27; GluN2B, H(1, 57) = 0.47, p = 0.49; GluN2C, H(1, 57) = 0.057, p = 0.81; GluN2D, H(1, 50) = 0.28, p = 0.60; GluN3A, H(1, 53) = 0.98, p = 0.32; GluD1, H(1, 58) = 2.07 p = 0.15; GluD2, H(1, 56) = 2.42, p = 0.12.

Figure 7

Expression of GABA-A channel subunit mRNAs in the putamen of control subjects (n = 29). The mRNA level of each subunit was normalized to reference gene ACTB and presented as mean ± SEM.

Figure 8

Expression of GABA-A channel subunits mRNA in the putamen of controls (n = 29) and alcoholics (n = 29). Data from each group is presented as scatter dot plot (°) with mean and 95% confidence interval and box and whiskers plot with median and whiskers plotted by Tukey method to determine outliers (•, above or below the whiskers). Statistical analysis was performed by excluding outliers. One Way ANOVA with Bonferroni post-hoc test, α1, df = 47, p = 0.64; α2, df = 47, p = 0.12; α6, df = 47, p = 0.15; β 1, df = 47, p = 0.14; β 2, df = 47, p = 0.40; β 3, df = 47, p = 0.55; δ, df = 47, p = 0.093. Kruskal–Wallis ANOVA on ranks with Dunn's post-hoc test, α3, H(1, 52) = 0.22, p = 0.64; α4, H(1, 57) = 0.98, p = 0.32; α5, H(1, 58) = 0.44, p = 0.51; ε, H(1, 53) = 0.14, p = 0.71; γ1, H(1, 53) = 0.27, p = 0.61; γ2, H(1, 56) = 0.20, p = 0.65; γ3, H(1, 55) = 1.51, p = 0.22; ρ 2, H(1, 58) = 2.00, p = 0.16; θ, H(1, 47) = 3.27, p = 0.071.

Figure 9

Comparison of GABA-A and ionotropic glutamate receptor subunit mRNAs in the caudate and putamen of controls (n = 29). Data from each group is presented as scatter dot plot (°) with mean and 95% confidence interval and box and whiskers plot with median and whiskers plotted by Tukey method to determine outliers (•, above or below the whiskers). Statistical analysis was performed by excluding outliers. One Way ANOVA with Bonferroni post-hoc test, GluA1, df = 52, p = 0.04; α2, df = 52, p = 0.11; α4, df = 52, p = 0.019; α5, df = 52, p = 0.79; α6, df = 52, p = 0.45; β 1, df = 52, p = 0.086; β 2, df = 52, p = 0.48; β 3, df = 52, p = 0.96; δ, df = 52, p = 0.77. Kruskal–Wallis ANOVA on ranks with Dunn's post-hoc test, GluA2, H(1, 55) = 0.48, p = 0.49; GluA3, H(1, 54) = 4.99, p = 0.026; GluA4, H(1, 56) = 3.34, p = 0.068; GluK1, H(1, 56) = 2.6, p = 0.11; GluK2, H(1, 54) = 2.48, p = 0.12; GluK3, H(1, 53) = 1.42, p = 0.23; GluK4, H(1, 53) = 0.0051, p = 0.94; GluK5, H(1, 56) = 7.31, p = 0.0069; GluN1, H(1, 56) = 5.23, p = 0.022; GluN2A, H(1, 56) = 10.28, p = 0.0013; GluN2B, H(1, 57) = 8.35, p = 0.0039; GluN2C, H(1, 55) = 0.19, p = 0.66; GluN2D, H(1, 52) = 5.06, p = 0.025; GluN3A, H(1, 52) = 4.83, p = 0.028; GluD1, H(1, 56) = 7.28, p = 0.007; GluD2, H(1, 53) = 8.33, p = 0.0039; α1, H(1, 49) = 23.62, p = 0.0000; α3, H(1, 50) = 1.47, p = 0.23; ε, H(1, 54) = 0.96, p = 0.33; γ 1, H(1, 53) = 7.03 p = 0.008; γ2, H(1, 58) = 6.31 p = 0.012; γ 3, H(1, 57) = 7.45 p = 0.0063; ρ 2, H(1, 57) = 2.20 p = 0.14; θ, H(1, 50) = 0.85 p = 0.36. *p < 0.05, **p < 0.01, ***p < 0.001.

#	Section	Preview
0	Introduction	In the mammalian brain the areas identified as caudate and putamen are parts of the striatum and…
1	Introduction	Glutamate and γ-aminobutyric acid (GABA) are the main excitatory and inhibitory neurotransmitters,…
2	Introduction	transmitter release. The delta receptors to-date have no clear role in neurons (Smart and Paoletti,…
3	Introduction	Alcohol is the most common drug of abuse in Western societies. Chronic, excessive alcohol…
4	Introduction	and tonic GABA transmission in neurons (Mihic et al., 1997; Sundstrom-Poromaa et al., 2002; Wallner…
5	Introduction	Alcohol-dependent disorders have been extensively studied in rodents but the human disorder is not…
6	Introduction	Here we have studied the changes that take place in the brains of alcoholics. We examined whether…
7	Materials and methods — Human samples	Twenty nine human controls and 29 individuals with from chronic alcohol dependence were included in…
8	Materials and methods — Human samples	brain samples were from the rostral putamen and caudate nucleus. The samples from the caudate…
9	Materials and methods — Total RNA isolation	Total RNA was isolated by using RNeasy Lipid Tissue Mini Kit (QIAGEN, Maryland, USA) and quantified…
10	Materials and methods — Quantitative real-time RT-PCR	Total RNA (200 ng) was reverse transcribed into cDNA in a 20 μl reaction mixture using Superscript…
11	Materials and methods — Quantitative real-time RT-PCR	identification of a single peak in the melting curve and a single band with the expected size on an…
12	Materials and methods — Quantitative real-time RT-PCR	(Schmittgen and Livak, 2008). Reference gene beta actin (ACTB) for putamen (expression stability…
13	Materials and methods — Statistical analysis	Statistical analysis was carried out using Statistica 11 and data were plotted with GraphPad Prism…
14	Results	The demographic characteristics of individuals in this study are shown in Table S2. There was no…
15	Results — Decreased expression of GluN2A but increased expression of GluD1 and GluD2 in the caudate nucleus of alcoholics	We examined the mRNA expression of the glutamate receptor subunits in the caudate from alcoholics…
16	Results — Decreased expression of GluN2A but increased expression of GluD1 and GluD2 in the caudate nucleus of alcoholics	We then examined the expression level between controls and alcoholics. The level of GluN2A mRNA was…
17	Results — Decreased expression of the δ, ε, and ρ2 but increased expression of the γ1 GABA-A subunit mRNAs in the caudate nucleus of alcoholics	We examined the mRNA expression of the GABA-A receptor subunits in the caudate from alcoholics and…
18	Results — Decreased expression of the δ, ε, and ρ2 but increased expression of the γ1 GABA-A subunit mRNAs in the caudate nucleus of alcoholics	The caudate levels of mRNAs encoding the δ, ϵ, and ρ2 subunits were significantly decreased…
19	Results — Unaltered mRNAs expression of glutamate and GABA-A receptor subunits in the putamen of alcoholics	We examined the mRNA expression of the glutamate and GABA-A receptor subunits in the putamen from…

Name	Type
abstainers	phenotype
ACTB	gene
addiction	phenotype
alcohol	phenotype
alcohol dependence	phenotype
Alcohol dependence group local	cohort
alcoholic brain local	cohort
alcoholism	phenotype
alcohol-related phenotypes	phenotype
Alcohol Use Disorder	phenotype
AMPA receptor	drug
amygdala	anatomy
automatic movements local	phenotype
automatic thinking local	phenotype
behavior change local	phenotype
Bio-Rad Experion local	drug
brain	anatomy
caudate nucleus	anatomy
chronic alcoholism	phenotype
cognition	phenotype
complex behaviors local	phenotype
conditioned aversion	phenotype
control	cohort
control group	cohort
controls	cohort
cortex	anatomy
Dorsal-lateral prefrontal cortex (DL-PFC) local	anatomy
dorsal striatum	anatomy
drug dependence	phenotype
ethanol consumption	phenotype
Eukaryote Total RNA StdSens assay local	drug
executive frontal areas local	anatomy
forebrain	anatomy
GABA	phenotype
GABA-A local	drug
GABA-A receptor local	drug
GABA-A receptor local	phenotype
GABA-A receptor genes local	gene
GABA-A receptors local	drug
GABA-A receptor subunits local	drug
Gabra1	gene
GABRA2	gene
GABRA3	gene
Gabra4	gene
GABRA5	gene
GABRA6	gene
GABRB1	gene
Gabrb2	gene
Gabrb3	gene
Gabrd	gene
GABRE	gene
Gabrg1	gene
Gabrg2	gene
Gabrg3	gene
GABRP	gene
GABRQ	gene
GABRR1	gene
GABRR2	gene
GABRR3	gene
glutamate	drug
glutamate subunits local	drug
goal-directed alcohol seeking local	phenotype
GRIA1	gene
GRIA2	gene
GRIA3	gene
GRIA4	gene
Grid1	gene
Grid2	gene
GRIK1	gene
GRIK2	gene
GRIK3	gene
GRIK4	gene
GRIK5	gene
GRIN1	gene
GRIN2A	gene
GRIN2B	gene
GRIN2C	gene
GRIN2D	gene
GRIN3A	gene
GRIN3B	gene
habits	phenotype
habitual alcohol use local	phenotype
hippocampus	anatomy
human brain	anatomy
Human post-mortem samples local	cohort
Impairment of executive and cognitive functions local	phenotype
inferior frontal gyrus	anatomy
intoxication	phenotype
Ionotropic glutamate receptor genes local	gene
JumpStart Taq DNA polymerase local	drug
kainate receptor	drug
lifetime alcohol use	phenotype
Liver cirrhosis	phenotype
long-term potentiation	phenotype
multi-drug abuse	phenotype
Nanodrop ND-1000 spectrophotometer local	drug
neuronal excitability	phenotype
neurosteroids	drug
New South Wales Tissue Resource Center local	cohort
NMDA receptor	drug
normal brain local	cohort
normal controls	cohort
orbitofrontal cortex	anatomy
prefrontal cortex	anatomy
premotor cortex	anatomy
Primary cortical motor areas local	anatomy
putamen	anatomy
RNA	drug
RNA integrity number (RIN)	phenotype
RNA quality indicator (RQI) local	phenotype
RNeasy Mini kit	drug
rodents	cohort
Rostral anterior cingulate local	anatomy
ROX reference dye local	drug
sensorimotor cortex	anatomy
smoking history	phenotype
Social drinker local	phenotype
striatum	anatomy
Superscript III reverse transcriptase	drug
SYBR green	drug
tonic inhibition	phenotype
University of Sydney	cohort
Wernicke–Korsakoff's syndrome local	phenotype
withdrawal	phenotype
γ-aminobutyric acid	drug

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In this knowledge base

Title	Year	PMID
Using human stem cells as a model system to understand the neural mechanisms of alcohol use disorders: Current status and outlook.	2019	30087005
Examining the effects of alcohol on GABA receptor mRNA expression and function in neural cultures generated from control and alcohol dependent donor induced pluripotent stem cells.	2018	29156239

External

Title	Authors	Journal	Year	Link
Glutamate delta-1 receptors regulate a tonic excitatory conductance in the mouse bed nucleus of the stria terminalis and influence neuronal function.	Conley SY et al.	—	2026	→
A new module in the drug development process: preclinical multi-center randomized controlled trial of R-ketamine on alcohol relapse.	Meinhardt MW et al.	—	2025	→
Glutamate delta-1 receptors regulate a novel tonic excitatory conductance in the mouse bed nucleus of the stria terminalis and influence neuronal function	Conley SY et al.	—	2025	—
Socioeconomic Status, Trauma, Cognitive Function, Impulsivity, Reward Salience, and Future Substance Use: Role of Left Caudate Connectivity with the Cingulo-Opercular Network.	Assari S et al.	—	2025	→
Differential regulation of G protein-coupled receptor-associated proteins in the caudate and the putamen of cynomolgus macaques following chronic ethanol drinking.	Neel AI et al.	—	2024	→
GABAergic mechanisms in alcohol dependence.	Uusi-Oukari M et al.	—	2024	→
Paradoxical Excitation Following Intravenous Lorazepam Administration for Alcohol Withdrawal - A Case Presentation and Literature Review.	Gonzalez J et al.	—	2023	→
Crosstalk Between GABAergic Neurotransmission and Inflammatory Cascades in the Post-ischemic Brain: Relevance for Stroke Recovery.	Michalettos G et al.	—	2022	→
GABA<sub>A</sub> receptor subtypes and benzodiazepine use, misuse, and abuse.	Engin E	—	2022	→
Hippocampal ceRNA networks from chronic intermittent ethanol vapor-exposed male mice and functional analysis of top-ranked lncRNA genes for ethanol drinking phenotypes.	Plasil SL et al.	—	2022	→
Effect of chronic ethanol consumption in rhesus macaques on the nucleus accumbens core transcriptome.	Walter N et al.	—	2021	→
Tonic GABA-activated synaptic and extrasynaptic currents in dentate gyrus granule cells and CA3 pyramidal neurons along the mouse hippocampal dorsoventral axis.	Netsyk O et al.	—	2020	→
Alteration in AMPA receptor subunit expression and receptor binding among patients with addictive disorders: A systematic review of human postmortem studies.	Ueno F et al.	—	2019	→
Using human stem cells as a model system to understand the neural mechanisms of alcohol use disorders: Current status and outlook.	Scarnati MS et al.	—	2019	→
Examining the effects of alcohol on GABA<sub>A</sub> receptor mRNA expression and function in neural cultures generated from control and alcohol dependent donor induced pluripotent stem cells.	Lieberman R et al.	—	2018	→
GABA<sub>A</sub> receptor polymorphisms in alcohol use disorder in the GWAS era.	Koulentaki M et al.	—	2018	→
Molecular, Neuronal, and Behavioral Effects of Ethanol and Nicotine Interactions.	Klenowski PM et al.	—	2018	→
On the relationships in rhesus macaques between chronic ethanol consumption and the brain transcriptome.	Iancu OD et al.	—	2018	→
The adjustment of γ-aminobutyric acid<sub>A</sub> tonic subunits in Huntington's disease: from transcription to translation to synaptic levels into the neostriatum.	Rosas-Arellano A et al.	—	2018	→
Alternative transcription of sodium/bicarbonate transporter SLC4A7 gene enhanced by single nucleotide polymorphisms.	Park HJ et al.	—	2017	→
Molecular Genetic Influences on Normative and Problematic Alcohol Use in a Population-Based Sample of College Students.	Webb BT et al.	—	2017	→
Glutamatergic plasticity and alcohol dependence-induced alterations in reward, affect and cognition.	Burnett EJ et al.	—	2016	→
Role of GABA(B) receptors in learning and memory and neurological disorders.	Heaney CF et al.	—	2016	→
Advances in Medications and Tailoring Treatment for Alcohol Use Disorder.	Seneviratne C et al.	—	2015	→
Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse.	Korpi ER et al.	—	2015	→