The overall objective of this INIA grant is to define mechanisms of alcohol avoidance and provide expertise in behavioral testing to other INIA investigators to evaluate ethanol-related behaviors in new mutant mice. Based on our data from the current period of INIA funding, we propose that the avoidance of high concentrations of ethanol by rodents is caused by increased release and/or production of proinflammatory cytokines in liver and brain and that these cytokines cause long-lasting changes in gene expression in the brain. We also found that initial high acceptance of alcohol can decrease when alcohol is presented continuously with intervening weekly abstinence periods, and this decrease depends upon the genetic background. We developed two genetic mouse models which maintain consistent high levels of preference and consumption (FVBxB6F1 mice; Sustained Alcohol Preference, SAP) or develop avoidance of alcohol (NZBxB6F1 mice; Reduced Alcohol Preference, RAP). These animal models provide the opportunity to compare brain gene expression profiles formed by initial alcohol consumption, sustained consumption and development of alcohol avoidance. To test the cytokine hypothesis, we will study: 1) ethanol consumption in knockout mice lacking genes for some proinflammatory cytokines and/or their receptors; 2) the effect of systemic treatment with proinflammatory cytokines (particularly a-TNF) and antagonists of cytokine receptors on voluntary ethanol consumption; 3) brain gene expression profiles after cytokine treatment to allow comparison with array data obtained from mice with ethanol avoidance; 4) treatment of FVBxB6F1 and NZBxB6F1 hybrid mice via 3 cycles of alcohol consumption and abstinence and identification of key genes by microarray analysis; 5) generation of brain regional knock-down mice of key genes by administration of RNAi. This work will use 3 INIA Cores (Texas Array and Informatics Core, RA Harris -PI; Colorado RNAi core, W. Zawada - PI; California Mouse Animal Model Core, A. Roberts - PI) and collaborations with six INIA investigators (A. Alcantara - Austin, Texas; S. Bergeson - Austin, Texas; R. D. Mayfield - Austin, Texas; R. Davis - Houston, Texas; A. Ryabinin - Portland, Oregon; B. Tabakoff - Aurora, Colorado). ? ? ?
| Blednov, Yuri A; Da Costa, Adriana J; Harris, R Adron et al. (2018) Apremilast Alters Behavioral Responses to Ethanol in Mice: II. Increased Sedation, Intoxication, and Reduced Acute Functional Tolerance. Alcohol Clin Exp Res 42:939-951 |
| Blednov, Yuri A; Da Costa, Adriana J; Tarbox, Tamara et al. (2018) Apremilast Alters Behavioral Responses to Ethanol in Mice: I. Reduced Consumption and Preference. Alcohol Clin Exp Res 42:926-938 |
| Blasio, Angelo; Wang, Jingyi; Wang, Dan et al. (2018) Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice. Biol Psychiatry 84:193-201 |
| McCarthy, Gizelle M; Farris, Sean P; Blednov, Yuri A et al. (2018) Microglial-specific transcriptome changes following chronic alcohol consumption. Neuropharmacology 128:416-424 |
| Erickson, Emma K; Farris, Sean P; Blednov, Yuri A et al. (2018) Astrocyte-specific transcriptome responses to chronic ethanol consumption. Pharmacogenomics J 18:578-589 |
| Most, Dana; Salem, Nihal A; Tiwari, Gayatri R et al. (2018) Silencing synaptic MicroRNA-411 reduces voluntary alcohol consumption in mice. Addict Biol : |
| McCarthy, Gizelle M; Warden, Anna S; Bridges, Courtney R et al. (2018) Chronic ethanol consumption: role of TLR3/TRIF-dependent signaling. Addict Biol 23:889-903 |
| Blednov, Yuri A; Black, Mendy; Chernis, Julia et al. (2017) Ethanol Consumption in Mice Lacking CD14, TLR2, TLR4, or MyD88. Alcohol Clin Exp Res 41:516-530 |
| Tulisiak, Christopher T; Harris, R Adron; Ponomarev, Igor (2017) DNA modifications in models of alcohol use disorders. Alcohol 60:19-30 |
| Mayfield, Jody; Harris, R Adron (2017) The Neuroimmune Basis of Excessive Alcohol Consumption. Neuropsychopharmacology 42:376 |
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