GABAergic gene expression in postmortem hippocampus from alcoholics and cocaine addicts; corresponding findings in alcohol-naïve P and NP rats.
paper
Cited
Public
- Authors
- Enoch, Mary-Anne; Zhou, Zhifeng; Kimura, Mitsuru; Mash, Deborah C; Yuan, Qiaoping; Goldman, David
- Year
- 2012
- Journal
- PloS one
- PMID
- 22253714
- DOI
- 10.1371/journal.pone.0029369
- PMCID
- PMC3258238
BACKGROUND: By performing identical studies in humans and rats, we attempted to distinguish vulnerability factors for addiction from neurobiological effects of chronic drug exposure. We focused on the GABAergic system within the hippocampus, a brain region that is a constituent of the memory/conditioning neuronal circuitry of addiction that is considered to be important in drug reinforcement behaviors in animals and craving and relapse in humans. METHODOLOGY: Using RNA-Seq we quantified mRNA transcripts in postmortem total hippocampus from alcoholics, cocaine addicts and controls and also from alcohol-naïve, alcohol preferring (P) and non-preferring (NP) rats selectively bred for extremes of alcohol-seeking behavior that also show a general addictive tendency. A pathway-targeted analysis of 25 GABAergic genes encoding proteins implicated in GABA synthesis, metabolism, synaptic transmission and re-uptake was undertaken. PRINCIPAL FINDINGS: Directionally consistent and biologically plausible overlapping and specific changes were detected: 14/25 of the human genes and 12/25 of the rat genes showed nominally significant differences in gene expression (global p values: 9×10⁻¹⁴, 7×10⁻¹¹ respectively). Principal FDR-corrected findings were that GABBR1 was down-regulated in alcoholics, cocaine addicts and P rats with congruent findings in NSF, implicated in GABAB signaling efficacy, potentially resulting in increased synaptic GABA. GABRG2, encoding the gamma2 subunit required for postsynaptic clustering of GABAA receptors together with GPHN, encoding the associated scaffolding protein gephryin, were both down-regulated in alcoholics and cocaine addicts but were both up-regulated in P rats. There were also expression changes specific to cocaine addicts (GAD1, GAD2), alcoholics (GABRA2) and P rats (ABAT, GABRG3). CONCLUSIONS/SIGNIFICANCE: Our study confirms the involvement of the GABAergic system in alcoholism but also reveals a hippocampal GABA input in cocaine addiction. Congruent findings in human addicts and P rats provide clues to predisposing factors for alcohol and drug addiction. Finally, the results of this study have therapeutic implications.
The Expression of Presynaptic/Synaptic GABAergic Genes in Human Samples and Rat Samples.ETOH = alcoholics; CO = cocaine addicts. Error bars: standard errors. ** FDR p<0.05; * FDR p≤0.06.
The Expression of GABAA Receptor Subunit Genes in Human Samples and Rat Samples.The genes are grouped in the chromosomal 4, 5 and 15 clusters. ETOH = alcoholics; CO = cocaine addicts. Error bars: standard errors. ** FDR p<0.05; * FDR p≤0.06.
The Expression of Genes Encoding GABAA Receptor Associated Proteins in Human Samples and Rat Samples.ETOH = alcoholics; CO = cocaine addicts. Error bars: standard errors. ** FDR p<0.05; * FDR p≤0.06.
Expression of GABAergic Pathway Genes in the Human Hippocampus: Cocaine Addicts vs. Controls.The genome-wide expression levels of 16,008 transcripts, including the 25 GABAergic genes, are shown.
A Summary of Gene Expression Changes in Human Samples and in P Rats Relative to NP Rats.This schematic summarizes the gene expression changes shown in Table 2 (FDR p≤0.06).
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| Name | Type |
|---|---|
| ABAT local | gene |
| addiction | phenotype |
| Addictive tendencies local | phenotype |
| Addictive tendency local | phenotype |
| adenosine base local | drug |
| African American | cohort |
| alcohol | phenotype |
| alcohol abuse | phenotype |
| alcohol dependence | phenotype |
| alcoholism | phenotype |
| Alcohol-naïve phenotype local | phenotype |
| Alcohol-preferring phenotype local | phenotype |
| alcohol-preferring rats | cohort |
| alcohol-related phenotypes | phenotype |
| alcohol tolerance | phenotype |
| Alcohol Use Disorder | phenotype |
| alcohol use disorders | phenotype |
| alcohol withdrawal | phenotype |
| amygdala | anatomy |
| anxiety | phenotype |
| baclofen | drug |
| benzodiazepines | drug |
| bipolar disorder | phenotype |
| brain pH | phenotype |
| brain tissue | anatomy |
| Caucasian/Hispanic local | cohort |
| Chronic heavy alcohol consumption local | phenotype |
| CNS | anatomy |
| cocaine | phenotype |
| Cocaine_Addiction local | phenotype |
| Cocaine intoxication local | phenotype |
| cocaine use disorder | phenotype |
| control | cohort |
| controls | cohort |
| Cornu Ammonis field CA1 local | anatomy |
| Cornu Ammonis field CA2 local | anatomy |
| Cornu Ammonis field CA3 local | anatomy |
| Cornu Ammonis field CA4 local | anatomy |
| craving | phenotype |
| Cultured rat hippocampal neurons local | cohort |
| Cynomolgus macaque monkeys local | cohort |
| default mode network | anatomy |
| dentate gyrus | anatomy |
| dependence | phenotype |
| DNA microarrays | drug |
| Drug and alcohol free local | phenotype |
| drug dependence | phenotype |
| drug-seeking behavior | phenotype |
| Enlarged liver local | phenotype |
| ethanol consumption | phenotype |
| ethanol dependence | phenotype |
| fatty liver | phenotype |
| frontal cortex | anatomy |
| GABA | phenotype |
| GABAA receptor | drug |
| GABAA receptor alpha subunit local | gene |
| GABAA receptor beta subunit local | gene |
| GABAA receptor gamma subunit local | gene |
| GABAB agonist local | drug |
| GABAB receptor | drug |
| GABAergic genes | gene |
| GABARAP | gene |
| Gabbr1 | gene |
| Gabbr2 | gene |
| GABRA2 | gene |
| GABRA6 | gene |
| GABRB1 | gene |
| Gabrb2 | gene |
| Gabrb3 | gene |
| Gabrg1 | gene |
| Gabrg2 | gene |
| Gabrg3 | gene |
| GAD1 | gene |
| GAD2 | gene |
| gene expression | phenotype |
| Generation S70 local | cohort |
| gene transcripts local | gene |
| GLS local | gene |
| glutamate | drug |
| Gphn | gene |
| Guanidinium thiocyanate local | drug |
| Hepatic fibrosis local | phenotype |
| High alcohol consuming mice local | cohort |
| high alcohol preference | phenotype |
| hippocampus | anatomy |
| human | cohort |
| Human postmortem samples local | cohort |
| humans | cohort |
| human samples | cohort |
| Indiana P rat local | cohort |
| Indiana P rats local | cohort |
| Klenow fragment | drug |
| learning behaviors local | phenotype |
| Low alcohol consuming mice local | cohort |
| low alcohol preference | phenotype |
| mice | cohort |
| National Association of Medical Examiners Committee on Cocaine-related Deaths local | cohort |
| neuronal excitability | phenotype |
| nicotine | drug |
| non-preferring (NP) rats local | cohort |
| Non-preferring phenotype local | phenotype |
| NP line rats local | cohort |
| NP rats | cohort |
| NSF local | gene |
| nucleus accumbens | anatomy |
| Oligo (dT)25 beads local | drug |
| Phenol-based RNA extraction solution local | drug |
| Phusion DNA polymerase local | drug |
| P line rats local | cohort |
| P/NP rats local | cohort |
| postmortem interval | phenotype |
| P rats | cohort |
| Rat postmortem samples local | cohort |
| rats | cohort |
| rat samples local | cohort |
| RDX local | gene |
| Relapse-like drinking | phenotype |
| Relapse vulnerability | phenotype |
| rewarding effect of drugs of abuse local | phenotype |
| RNA-seq | drug |
| RNeasy spin columns local | drug |
| schizophrenia | phenotype |
| Seizure threshold local | phenotype |
| SLC32A1 | gene |
| SLC6A1 | gene |
| SLC6A11 | gene |
| subiculum | anatomy |
| T4 DNA polymerase local | drug |
| T4 polynucleotide kinase | drug |
| Theta currents local | phenotype |
| tiagabine local | drug |
| tolerance | phenotype |
| UBQLN1 local | gene |
| universal adaptor local | drug |
| University of Miami | cohort |
| University of Miami Brain Bank local | cohort |
| VGAT | gene |
| water | drug |
| Wistar rats | cohort |
| withdrawal | phenotype |
| ZDHHC3 local | gene |
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