A cluster of differentially expressed signal transduction genes identified by microarray analysis in a rat genetic model of alcoholism

Abstract

Analyzing gene expression patterns in genetic models of alcoholism may uncover previously unknown susceptibility genes, and point to novel targets for drug development. Here, we compared expression profiles in alcoholpreferring AA rats with the alcohol-avoiding counterpart ANA line, and unselected Wistar rats. Cingulate cortex, Nc. accumbens, amygdala and hippocampus of each line were analyzed using the Afymetrix RN U34 arrays and dChip 1.1 software. Analysis of line-specific expression revealed 48 differentially expressed genes between AA and ANA rats. Elevated hippocampal neuropeptide Y (NPY) was found in ANA rats in agreement with previous studies. A cluster of MAP-kinases indicating altered signal transduction was upregulated within the Nc. Accumbens of the AA line, and is of particular functional interest. Within the amygdala, a more loosely inter-related cluster of cytoskeleton-associated genes may point to structural abnormalities. The observed dysregulations may contribute to the alcohol-preferring phenotype.

Genetic Impairment of Frontocortical Endocannabinoid Degradation and High Alcohol Preference

“…The differential prefrontal endocannabinoid activity shown here adds to a list of neurochemical and genetic traits which have segregated through selective breeding of the AA and ANA lines (Sinclair et al, 1989;Gianoulakis et al, 1992;Arlinde et al, 2004). Most of these are likely results of random cosegregation.…”

“…Brain expression profiling further points to the possibility that dysregulated expression of endocannabinoid genes, and signal transduction genes under their control, could contribute to high alcohol preference (Rimondini et al, 2002;Arlinde et al, 2004;Derkinderen et al, 2001).…”

“…AA rats also share some interesting behavioral traits with early onset alcoholism, which has a distinct heritability and pharmacogenomic profile (Johnson et al, 2000;Cloninger, 1987;Möller et al, 1997). The AA and ANA lines have diverged with respect to several neurochemical measures (Sinclair et al, 1989;Gianoulakis et al, 1992;Arlinde et al, 2004), but the factors causing differential alcohol self-administration between them remain largely unknown.…”

The Neurometabolic Fingerprint of Excessive Alcohol Drinking

“…These studies have led to new mechanistic insights and novel candidate genes for disease mechanisms, but when applied to psychiatric disorders the discriminative power of brain transcriptome profiles to separate cases and controls has typically been low (Reimers et al, 2005). We and others have used this approach to identify sustained gene expression patterns in the corticostriatal circuitry induced by chronic alcohol exposure, consumption, and dependence (Mayfield et al, 2002;Rimondini et al, 2002;Arlinde et al, 2004;Sommer et al, 2005;Liu et al, 2006;Meinhardt et al, 2013). Generally, these experiments resulted in interesting and verifiable candidate genes, but could not demonstrate robust discrimination of cases and controls based on their global gene expression profiles.…”

The effect of alcohol and nicotine abuse on gene expression in the brain

“…Arlinde et al (37) compared gene expression in the NAC, hippocampus, cingulated cortex and AMYG of noncongenital alcohol-preferring, alcohol non-preferring and non-selected Wistar rat strains using Affimetrix arrays containing probes for 1000 genes. Forty-eight genes were found to be differentially expressed between the alcoholpreferring and alcohol non-preferring rat strains.…”