Abstracts - Speakers
First Annual Waggoner Center Advance - March 22, 2013
Yuri Blednov, MD/PhD
Research Scientist, Waggoner Center for Alcohol & Addiction Research
From Concept to Drugs: Neuroimmune Gene Expression, Alcohol Consumption, and Potential Intervention
Genes classified as "immune/stress response" form one of the most prominent functional groups with differential expression in the frontal cortex and VTA of alcoholics in comparison to non-alcoholics (Liu et al., 2006; Flatscher-Bader et al., 2006), and brain gene expression in mice that are genetically predisposed to alcohol consumption implicates pro-inflammatory mediators in brain that may regulate alcohol intake (Mulligan et al., 2006). Based on these gene expression profiles, we selected six genes - beta-2-microglobulin (B2m), cathepsin S (Ctss), cathepsin F (Ctsf), interleukin 1 receptor antagonist (Il1rn), CD14 molecule (Cd14) and interleukin 6 (Il6) - for behavioral validation using null mutant mice. Ethanol consumption and preference were reduced in all the null mutant mice in the 24-hour two-bottle choice test, the test that was the basis for selection of these genes. No major differences were observed in consumption of saccharin in the null mutant mice. Deletion of B2m, Ctss, Il1rn, Cd14 and Il6 also reduced ethanol consumption in the two tests with limited alcohol (with some variation between tests) (Blednov et al., 2012). We next asked if activation of the immune system could promote excessive alcohol consumption. We found that activation of inflammatory TLR4 signaling (lipolysaccharide, LPS, 1 mg/kg, i.p., C57/Bl6 mice) promotes alcohol consumption. This effect persisted at least 3 months after a single LPS treatment. No changes in taste (sweet or bitter) perception, palatability (sucrose intake) or olfactory recognition were found after LPS-pre-treatment. The lack of CD14, a key component of TLR4 signaling (CD14 knockout mice) prevented the increase of alcohol intake after treatment with LPS (Blednov et al., 2011). Next we asked if pharmacological blockade of the TLR-pathway and other known anti-inflammatory medications can reduce ethanol intake. Reduction of alcohol intake in mice was shown: 1) by inhibition of IKK-beta the key element of TLR-pathway, with TPCA-1 (50 mg/kg); 2) by inhibitors of phosphodiesterase-4 (but not other classes of this enzyme); 3) by activation of peroxisome proliferator-activated receptors type alpha and gamma (but not delta). Taken together, these results provide the most compelling evidence to date that global gene expression analysis can identify novel genetic determinants of complex behavioral traits. Specifically, they suggest a novel role for neuroimmune signaling in regulation of alcohol consumption and provide some promising targets for pharmacological intervention. Supported by the National Institute on Alcohol Abuse and Alcoholism, (AA U01 13520 - INIA Project; and AA06399).