Alcoholism is a health disorder characterized by a progression from experimentation, to excessive intake, and ultimately alcohol dependence accompanied by compulsive alcohol consumption. The relationship between alcohol consumption and dependence is complex. For example, it is assumed that increased alcohol intake associated with alcohol dependence leads to increased symptoms of physical withdrawal. However, studies performed in the PARC showed that natural genetic variants (e.g. inbred mouse strains) with increased susceptibility to high alcohol withdrawal convulsions tend to avoid alcohol consumption. More recent PARC studies found a strong positive genetic correlation between measures of behavioral disinhibition in the Go/No-go task with measures of alcohol withdrawal severity. This component uses a candidate gene approach to test the contribution of the corticotropin releasing factor (CRF) system to these relationships. The CRF system is known to contribute to mechanisms surrounding alcohol dependence. Our preliminary studies suggest that the CRF system is involved in regulation of alcohol withdrawal and behavioral inhibition. The CRF system contains four peptides: CRF, urocortin (Ucn)1, Ucn2 and Ucn3, two types of CRF receptors, and the CRF-binding protein. The role of genes encoding these peptides and proteins in ethanol withdrawal or in impulsive behaviors has not been investigated. The four aims of this component propose to bridge this gap by: 1) investigating withdrawal-induced convulsions after acute and chronic ethanol in CRF, Ucnl, CRFI receptor, CRF2 receptor KO mice and their wildtype (WT) llttermates, 2) investigating behavioral inhibition in the Go/No-go task in CRF, Ucnl, CRFI receptor, CRF2 receptor KO mice, and their WT llttermates, 3) identifying gene networks contributing to regulation of behavioral inhibition and alcohol withdrawal by expression microarray analysis in CRF, Ucnl, CRFI receptor, CRF2 receptor KO mice and their WT controls, 4) identifying polymorphisms in genes encoding CRF, Ucnl, Ucn2, Ucn3, CRFI, CRF2 and CRF-BP in inbred strains of mice known to have differences in signs of ethanol-induced withdrawal and measures of disinhibition in the Go/No-go task, and to test associations of these polymorphisms with these and other ethanol-related phenotypes.
The proposed studies address PARC aims of understanding genetic mechanisms regulating withdrawal from chronic alcohol and decrease impulse control associated with alcoholism. Understanding these mechanisms will contribute to future development of individualized pharmacotherapies and prevention policies of this devastating disorder.
|Mangold, Colleen A; Wronowski, Benjamin; Du, Mei et al. (2017) Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging. J Neuroinflammation 14:141|
|Nimitvilai, Sudarat; Uys, Joachim D; Woodward, John J et al. (2017) Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques. J Neurosci 37:3646-3660|
|Hasler, Brant P; Franzen, Peter L; de Zambotti, Massimiliano et al. (2017) Eveningness and Later Sleep Timing Are Associated with Greater Risk for Alcohol and Marijuana Use in Adolescence: Initial Findings from the National Consortium on Alcohol and Neurodevelopment in Adolescence Study. Alcohol Clin Exp Res 41:1154-1165|
|Allen, Daicia C; Ford, Matthew M; Grant, Kathleen A (2017) Cross-Species Translational Findings in the Discriminative Stimulus Effects of Ethanol. Curr Top Behav Neurosci :|
|Colville, A M; Iancu, O D; Oberbeck, D L et al. (2017) Effects of selection for ethanol preference on gene expression in the nucleus accumbens of HS-CC mice. Genes Brain Behav 16:462-471|
|Jones, Scott A; Steele, Joel S; Nagel, Bonnie J (2017) Binge drinking and family history of alcoholism are associated with an altered developmental trajectory of impulsive choice across adolescence. Addiction 112:1184-1192|
|Böger, Carsten A; Gorski, Mathias; McMahon, Gearoid M et al. (2017) NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality. J Am Soc Nephrol 28:2311-2321|
|Beattie, Matthew C; Maldonado-Devincci, Antoniette M; Porcu, Patrizia et al. (2017) Voluntary ethanol consumption reduces GABAergic neuroactive steroid (3?,5?)3-hydroxypregnan-20-one (3?,5?-THP) in the amygdala of the cynomolgus monkey. Addict Biol 22:318-330|
|Jimenez, Vanessa A; Allen, Daicia C; McClintick, Megan N et al. (2017) Social setting, social rank and HPA axis response in cynomolgus monkeys. Psychopharmacology (Berl) 234:1881-1889|
|Buck, Kari J; Chen, Gang; Kozell, Laura B (2017) Limbic circuitry activation in ethanol withdrawal is regulated by a chromosome 1 locus. Alcohol 58:153-160|
Showing the most recent 10 out of 277 publications