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.
|Xu, Ting; Falchier, Arnaud; Sullivan, Elinor L et al. (2018) Delineating the Macroscale Areal Organization of the Macaque Cortex In Vivo. Cell Rep 23:429-441|
|Iancu, Ovidiu D; Colville, Alexander; Walter, Nicole A R et al. (2018) On the relationships in rhesus macaques between chronic ethanol consumption and the brain transcriptome. Addict Biol 23:196-205|
|Morales, Angelica M; Jones, Scott A; Ehlers, Alissa et al. (2018) Ventral striatal response during decision making involving risk and reward is associated with future binge drinking in adolescents. Neuropsychopharmacology 43:1884-1890|
|Gavin, David P; Hashimoto, Joel G; Lazar, Nathan H et al. (2018) Stable Histone Methylation Changes at Proteoglycan Network Genes Following Ethanol Exposure. Front Genet 9:346|
|Purohit, Kush; Parekh, Puja K; Kern, Joseph et al. (2018) Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge-Like Alcohol Drinking in Mice. Alcohol Clin Exp Res 42:879-888|
|Müller-Oehring, Eva M; Kwon, Dongjin; Nagel, Bonnie J et al. (2018) Influences of Age, Sex, and Moderate Alcohol Drinking on the Intrinsic Functional Architecture of Adolescent Brains. Cereb Cortex 28:1049-1063|
|Iancu, Ovidiu Dan; Colville, Alex M; Wilmot, Beth et al. (2018) Gender-Specific Effects of Selection for Drinking in the Dark on the Network Roles of Coding and Noncoding RNAs. Alcohol Clin Exp Res :|
|Kafkafi, Neri; Agassi, Joseph; Chesler, Elissa J et al. (2018) Reproducibility and replicability of rodent phenotyping in preclinical studies. Neurosci Biobehav Rev 87:218-232|
|Qiu, J; Wagner, E J; Rønnekleiv, O K et al. (2018) Insulin and leptin excite anorexigenic pro-opiomelanocortin neurones via activation of TRPC5 channels. J Neuroendocrinol 30:|
|Allen, Daicia C; Ford, Matthew M; Grant, Kathleen A (2018) Cross-Species Translational Findings in the Discriminative Stimulus Effects of Ethanol. Curr Top Behav Neurosci 39:95-111|
Showing the most recent 10 out of 291 publications