Abstract
Chronically available alcohol escalates drinking in mice and a single injection of the immune activator lipopolysaccharide can mimic this effect and result in a persistent increase in alcohol consumption. We hypothesized that chronic alcohol drinking and lipopolysaccharide injections will produce some similar molecular changes that play a role in regulation of alcohol intake. We investigated the molecular mechanisms of chronic alcohol consumption or lipopolysaccharide insult by gene expression profiling in prefrontal cortex and liver of C57BL/6J mice. We identified similar patterns of transcriptional changes among four groups of animals, three consuming alcohol (vs water) in different consumption tests and one injected with lipopolysaccharide (vs. vehicle). The three tests of alcohol consumption are the continuous chronic two bottle choice (Chronic), two bottle choice available every other day (Chronic Intermittent) and limited access to one bottle of ethanol (Drinking in the Dark). Gene expression changes were more numerous and marked in liver than in prefrontal cortex for the alcohol treatments and similar in the two tissues for lipopolysaccharide. Many of the changes were unique to each treatment, but there was significant overlap in prefrontal cortex for Chronic-Chronic Intermittent and for Chronic Intermittent-lipopolysaccharide and in liver all pairs showed overlap. In silico cell-type analysis indicated that lipopolysaccharide had strongest effects on brain microglia and liver Kupffer cells. Pathway analysis detected a prefrontal cortex-based dopamine-related (PPP1R1B, DRD1, DRD2, FOSB, PDNY) network that was highly over-represented in the Chronic Intermittent group, with several genes from the network being also regulated in the Chronic and lipopolysaccharide (but not Drinking in the Dark) groups. Liver showed a CYP and GST centered metabolic network shared in part by all four treatments. We demonstrate common consequences of chronic alcohol consumption and immune activation in both liver and brain and show distinct genomic consequences of different types of alcohol consumption.
Highlights
Effects of chronic consumption of alcohol and other drugs of abuse include tolerance and dependence and these neuroadaptations arise, at least in part, from changes in gene expression [1,2]
These results are consistent with previous publications [31,45]. Mice increased their consumption of ethanol over time as indicated by a significant difference between the first and last four sessions (Figure 1B). (Percent increase and paired t test, chronic two bottle choice (Chronic), 24% increase, p = 0.05; chronic intermittent (CI), 59% increase, p = 6.4E–04; drinking in the dark (DID), 46% increase, p = 1.4E–04)
The CI test was originally derived from studies in rats that showed a marked escalation of alcohol consumption with every other day access [23] and CI, but not Chronic, drinking is inhibited by chlorzoxazone [22] indicating differences in the neurobiological mechanisms underlying these two drinking tests
Summary
Effects of chronic consumption of alcohol and other drugs of abuse include tolerance and dependence and these neuroadaptations arise, at least in part, from changes in gene expression [1,2]. Drug development requires testing in animal models and there is only limited information on brain gene expression changes in rodent models of chronic alcohol consumption [1]. Mice are widely used to study alcohol consumption but analyses of brain gene expression profiles following chronic alcohol drinking are remarkably limited for mouse models [1,9,10] and there are no direct comparisons of genomic changes in different animal models. Activation of the innate immune system with LPS and the availability of chronic ethanol both increase alcohol consumption [14,15] This raises the question of which, if any, of the rodent models of excessive alcohol consumption show changes in gene expression, neuroimmune genes, in particular, that might be similar to human alcoholism and similar to the immune activation produced by LPS. A few studies have examined changes in liver gene expression produced by administration of alcohol by chronic intragastric infusion or consumption of a liquid diet [16,17], but there is a paucity of studies of liver gene expression profiles in any of the mouse models of voluntary alcohol consumption
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