Involvement of the limbic basal ganglia in ethanol withdrawal convulsivity in mice is influenced by a chromosome 4 locus.
- Authors
- Chen, Gang; Kozell, Laura B; Hitzemann, Robert; Buck, Kari J
- Year
- 2008
- Journal
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- PMID
- 18815268
- DOI
- 10.1523/JNEUROSCI.1713-08.2008
- PMCID
- PMC3276309
Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force that sustains ethanol (alcohol) use/abuse and may contribute to relapse in alcoholics. Although no animal model duplicates alcoholism, models for specific factors, like the withdrawal syndrome, are useful for identifying potential genetic and neural determinants of liability in humans. We generated congenic mice that confirm a quantitative trait locus (QTL) on chromosome 4 with a large effect on predisposition to alcohol withdrawal. Using c-Fos expression as a high-resolution marker of neuronal activation, congenic mice demonstrated significantly less neuronal activity associated with ethanol withdrawal than background strain mice in the substantia nigra pars reticulata (SNr), subthalamic nucleus (STN), rostromedial lateral globus pallidus, and ventral pallidum. Notably, neuronal activation in subregions of the basal ganglia associated with limbic function was more intense than in subregions associated with sensorimotor function. Bilateral lesions of caudolateral SNr attenuated withdrawal severity after acute and repeated ethanol exposures, whereas rostrolateral SNr and STN lesions did not reduce ethanol withdrawal severity. Caudolateral SNr lesions did not affect pentylenetetrazol-enhanced convulsions. Our results suggest that this QTL impacts ethanol withdrawal via basal ganglia circuitry associated with limbic function and that the caudolateral SNr plays a critical role. These are the first analyses to elucidate circuitry by which a confirmed addiction-relevant QTL influences behavior. This mouse QTL is syntenic with human chromosome 9p. Given the growing body of evidence that a gene(s) on chromosome 9p influences alcoholism, our results can facilitate human research on alcohol dependence and withdrawal.
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| Alcohol effects on associative and sensorimotor cortico-thalamo-basal ganglia circuits alter decision making and alcohol intake. | Lovinger DM | — | 2025 | → |
| Endoplasmic reticulum and Golgi stress in microcephaly. | Passemard S et al. | — | 2019 | → |
| Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference. | Kozell LB et al. | — | 2018 | → |
| Limbic circuitry activation in ethanol withdrawal is regulated by a chromosome 1 locus. | Buck KJ et al. | — | 2017 | → |
| Genetics and genomics of alcohol sensitivity. | Morozova TV et al. | — | 2014 | → |
| Mpdz expression in the caudolateral substantia nigra pars reticulata is crucially involved in alcohol withdrawal. | Kruse LC et al. | — | 2014 | → |
| Dopamine D1 receptor signaling system regulates ryanodine receptor expression in ethanol physical dependence. | Kurokawa K et al. | — | 2013 | → |
| Modeling the diagnostic criteria for alcohol dependence with genetic animal models. | Crabbe JC et al. | — | 2013 | → |
| mGluR7 genetics and alcohol: intersection yields clues for addiction. | Gyetvai B et al. | — | 2011 | → |
| Striatal involvement in human alcoholism and alcohol consumption, and withdrawal in animal models. | Chen G et al. | — | 2011 | → |
| Substantia nigra pars reticulata is crucially involved in barbiturate and ethanol withdrawal in mice. | Chen G et al. | — | 2011 | → |
| Genetic research: who is at risk for alcoholism. | Foroud T et al. | — | 2010 | → |
| Rostroventral caudate putamen involvement in ethanol withdrawal is influenced by a chromosome 4 locus. | Chen G et al. | — | 2010 | → |
| Differential activation of limbic circuitry associated with chronic ethanol withdrawal in DBA/2J and C57BL/6J mice. | Chen G et al. | — | 2009 | → |
| Mapping a barbiturate withdrawal locus to a 0.44 Mb interval and analysis of a novel null mutant identify a role for Kcnj9 (GIRK3) in withdrawal from pentobarbital, zolpidem, and ethanol. | Kozell LB et al. | — | 2009 | → |