Modeling the Diagnostic Criteria for Alcohol Dependence with Genetic Animal Models

Crabbe, John C.; Kendler, Kenneth S.; Hitzemann, Robert

doi:10.1007/7854_2011_162

Cited by 18 publications

(18 citation statements)

References 126 publications

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ These concentrations were chosen to ensure sedation, which is reported to occur at >2.5 g/kg of alcohol 41 . Both groups of WT and KO mice had similar latency to onset of LORR (Fig.…”

Section: Increased Reward Potency Of Alcohol By Nbcn1 Lossmentioning

confidence: 99%

Increased Alcohol Consumption in Mice Lacking Sodium Bicarbonate Transporter NBCn1

Schank

Lee

González-Islas

et al. 2020

Sci Rep

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christian Aalkjaer 5 , ebbe Boedtkjer 5 & inyeong choi 2 ✉ The previous reports on an addiction vulnerability marker in the human SLC4A7 gene encoding the na/Hco 3 transporter NBCn1 suggest that this pH-regulating protein may affect alcohol-related behavior and response. Here, we examined alcohol consumption and sensitivity to the sedative effects of alcohol in male NBCn1 knockout mice. These mice displayed lower pH in neurons than wildtype controls, determined by intracellular pH in hippocampal neuronal cultures. neurons from knockout mice had a higher action potential threshold and a more depolarized membrane potential, thus reducing membrane excitability. in a two-bottle free choice procedure, knockout mice consumed more alcohol than controls and consistently increased alcohol consumption after repeated alcohol deprivation periods. Quinine and sucrose preference was similar between genotypes. Knockout mice showed increased propensity for alcohol-induced conditioned place preference. In loss of righting reflex assessment, knockout mice revealed increased sensitivity to alcohol-induced sedation and developed tolerance to the sedation after repeated alcohol administrations. furthermore, chronic alcohol consumption caused NBCn1 downregulation in the hippocampus and striatum of mice and humans. These results demonstrate an important role of NBCn1 in regulation of alcohol consumption and sensitivity to alcohol-induced sedation. pH is a broad but important biological factor that can cause significant changes in brain function 1,2. pH can change activities of numerous proteins such as neurotransmitter receptors, ion channels, and synaptic transmission machinery proteins, and such changes perturb membrane excitability, firing properties, and intracellular signaling cascades 3,4. The physiological importance of pH in neurons has been documented 5,6 ; nonetheless, it is presently unclear whether pH affects reward, motivation and addiction. In the field of addiction research, pH disturbance has been viewed as the consequence of drug action or metabolism 7. For example, the risk of metabolic acidosis is increased by an overdose of drugs including cocaine, heroin, and ecstasy 8. Metabolic acidosis is also induced by chronic or heavy alcohol consumption 9,10. This metabolic complication is due to the conversion of alcohol to ketone bodies such as β-hydroxybutyrate, thus consuming HCO 3 −. For example, a study shows that about 25% of alcoholic admissions in hospitals have ketogenic acidosis 11 , which affects many organ functions. Nonetheless, little is known whether pH conversely affects drug consumption or drug-induced response. NBCn1 (SLC4A7) is a pH-regulating plasma membrane protein found in a variety of tissues 12. In most neurons, NBCn1 is predominantly localized to postsynaptic membranes 13 , where it transports Na + and HCO 3 − into neurons and buffers intracellular H +. Thus, the transporter regulates intracellular pH (pH i) in postsynaptic neurons and extracellular pH (pH o) in the synaptic cleft. Genome-wide assoc...

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Section: Increased Reward Potency Of Alcohol By Nbcn1 Lossmentioning

confidence: 99%

Increased Alcohol Consumption in Mice Lacking Sodium Bicarbonate Transporter NBCn1

Schank

Lee

González-Islas

et al. 2020

Sci Rep

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“…Alcohol-dependent disorders have been extensively studied in rodents but the human disorder is not fully mimicked by these models (Crabbe et al, 2013 ). A few studies have been conducted on post-mortem brain samples from alcoholics (Lewohl et al, 1997 , 2001 ; Dodd and Lewohl, 1998 ; Buckley et al, 2000 , 2006 ; Mayfield et al, 2002 ; Buckley and Dodd, 2004 ; Dodd et al, 2004 ; Flatscher-Bader et al, 2005 , 2006 ; Kalsi et al, 2009 ; Jin et al, 2011a , 2014a , b ; Domart et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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

Bhandage

Jin

Bazov

et al. 2014

Front. Cell. Neurosci.

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Chronic consumption of alcohol by humans has been shown to lead to impairment of executive and cognitive functions. Here, we have studied the mRNA expression of ion channel receptors for glutamate and GABA in the dorsal striatum of post-mortem brains from alcoholics (n = 29) and normal controls (n = 29), with the focus on the caudate nucleus that is associated with the frontal cortex executive functions and automatic thinking and on the putamen area that is linked to motor cortices and automatic movements. The results obtained by qPCR assay revealed significant changes in the expression of specific excitatory ionotropic glutamate and inhibitory GABA-A receptor subunit genes in the caudate but not the putamen. Thus, in the caudate we found reduced levels of mRNAs encoding the GluN2A glutamate receptor and the δ, ε, and ρ2 GABA-A receptor subunits, and increased levels of the mRNAs encoding GluD1, GluD2, and GABA-A γ1 subunits in the alcoholics as compared to controls. Interestingly in the controls, 11 glutamate and 5 GABA-A receptor genes were more prominently expressed in the caudate than the putamen (fold-increase varied from 1.24 to 2.91). Differences in gene expression patterns between the striatal regions may underlie differences in associated behavioral outputs. Our results suggest an altered balance between caudate-mediated voluntarily controlled and automatic behaviors in alcoholics, including diminished executive control on goal-directed alcohol-seeking behavior.

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“…Laboratory animals have been used to model various aspects of the addictive process and such studies have shown substantial genetic variability across many phenotypes hypothesized to be important (Crabbe, 2008; Crabbe, Kendler & Hitzemann, 2013; Crabbe & Phillips, 2004). One phenotype domain of particular interest comprises the reinforcing/rewarding and punishing/aversive effects of ethanol, reflecting the belief that vulnerability to addiction depends, in part, on genetic variation in sensitivity to these effects (Tabakoff & Hoffman, 1988).…”

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confidence: 99%

Genetic relationship between ethanol-induced conditioned place preference and other ethanol phenotypes in 15 inbred mouse strains.

Cunningham

2014

Behavioral Neuroscience

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The genetic relationships between different behaviors used to index the rewarding or reinforcing effects of alcohol are poorly understood. To address this issue, ethanol-induced conditioned place preference (CPP) was tested in a genetically diverse panel of inbred mouse strains and strain means from this study and other inbred strain studies were used to examine the genetic correlation between CPP and several ethanol-related phenotypes, including activity measures recorded during CPP training and testing. Mice from each strain were exposed to a well-characterized unbiased place conditioning procedure using ethanol doses of 2 or 4 g/kg; an additional group from each strain was exposed to saline alone on all trials. Genotype had a significant effect on CPP, basal locomotor activity, ethanol-stimulated activity and the effect of repeated ethanol exposure on activity. Correlational analyses showed significant negative genetic correlations between CPP and sweetened ethanol intake and between CPP and test session activity, as well as a significant positive genetic correlation between CPP and chronic ethanol withdrawal severity. Moreover, there was a trend toward a positive genetic correlation between CPP and ethanol-induced conditioned taste aversion. These genetic correlations suggest overlap in the genetic mechanisms underlying CPP and each of these traits. The patterns of genetic relationships suggest a greater impact of ethanol’s aversive effects on drinking and a greater impact of ethanol’s rewarding effects on CPP. Overall, these data support the idea that genotype influences ethanol’s rewarding effect, a factor that may contribute importantly to addictive vulnerability.

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Modeling the Diagnostic Criteria for Alcohol Dependence with Genetic Animal Models

Cited by 18 publications

References 126 publications

Increased Alcohol Consumption in Mice Lacking Sodium Bicarbonate Transporter NBCn1

Increased Alcohol Consumption in Mice Lacking Sodium Bicarbonate Transporter NBCn1

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

Genetic relationship between ethanol-induced conditioned place preference and other ethanol phenotypes in 15 inbred mouse strains.

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