Abstract
BackgroundThe inability to reduce or regulate alcohol intake is a hallmark symptom for alcohol use disorders. Research on novel behavioral and genetic models of experience-induced changes in drinking will further our knowledge on alcohol use disorders. Distinct alcohol self-administration behaviors were previously observed when comparing two F1 hybrid strains of mice: C57BL/6J x NZB/B1NJ (BxN) show reduced alcohol preference after experience with high concentrations of alcohol and periods of abstinence while C57BL/6J x FVB/NJ (BxF) show sustained alcohol preference. These phenotypes are interesting because these hybrids demonstrate the occurrence of genetic additivity (BxN) and overdominance (BxF) in ethanol intake in an experience dependent manner. Specifically, BxF exhibit sustained alcohol preference and BxN exhibit reduced alcohol preference after experience with high ethanol concentrations; however, experience with low ethanol concentrations produce sustained alcohol preference for both hybrids. In the present study, we tested the hypothesis that these phenotypes are represented by differential production of the inducible transcription factor, ΔFosB, in reward, aversion, and stress related brain regions.ResultsChanges in neuronal plasticity (as measured by ΔFosB levels) were experience dependent, as well as brain region and genotype specific, further supporting that neuronal circuitry underlies motivational aspects of ethanol consumption. BxN mice exhibiting reduced alcohol preference had lower ΔFosB levels in the Edinger-Westphal nucleus than mice exhibiting sustained alcohol preference, and increased ΔFosB levels in central medial amygdala as compared with control mice. BxN mice showing sustained alcohol preference exhibited higher ΔFosB levels in the ventral tegmental area, Edinger-Westphal nucleus, and amygdala (central and lateral divisions). Moreover, in BxN mice ΔFosB levels in the Edinger-Westphal nucleus and ventral tegmental regions significantly positively correlated with ethanol preference and intake. Additionally, hierarchical clustering analysis revealed that many ethanol-naïve mice with overall low ΔFosB levels are in a cluster, whereas many mice displaying sustained alcohol preference with overall high ΔFosB levels are in a cluster together.ConclusionsBy comparing and contrasting two alcohol phenotypes, this study demonstrates that the reward- and stress-related circuits (including the Edinger-Westphal nucleus, ventral tegmental area, amygdala) undergo significant plasticity that manifests as reduced alcohol preference.
Highlights
The inability to reduce or regulate alcohol intake is a hallmark symptom for alcohol use disorders
Reduced alcohol preference would be the opposite of an alcohol deprivation effect and sustained alcohol preference could be described as the absence of an alcohol deprivation effect
This study demonstrates that mice exhibiting reduced alcohol preference show significant plasticity in reward- and stress-related circuits
Summary
The inability to reduce or regulate alcohol intake is a hallmark symptom for alcohol use disorders. Distinct alcohol self-administration behaviors were previously observed when comparing two F1 hybrid strains of mice: C57BL/6J x NZB/B1NJ (BxN) show reduced alcohol preference after experience with high concentrations of alcohol and periods of abstinence while C57BL/6J x FVB/NJ (BxF) show sustained alcohol preference. We found that C57BL/ 6JxFVB/NJ (BxF) and FVB/NJxC57BL/6J (FVBxB6) F1 hybrid mice self-administer unusually high levels of alcohol during two-bottle preference tests (females consume 20–35 g/kg/day and males 7–25 g/kg/day, depending on concentration and paradigm) [4] This new genetic model has a significant advantage when compared to existing inbred strains, including evidence of an overdominant phenotype and drinking to high blood alcohol levels [4]. Identification of differential immediate early gene expression for these hybrids offers insight into the brain circuitry important for the rewarding and aversive properties of ethanol
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