Chronic self-administration of alcohol results in elevated ΔFosB: comparison of hybrid mice with distinct drinking patterns

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.

Dynamic c‐Fos changes in mouse brain during acute and protracted withdrawal from chronic intermittent ethanol exposure and relapse drinking

“…Although the majority of areas analyzed showed no differences in baseline c‐Fos expression at this prolonged withdrawal time point, it is possible that one or more areas would show either enhanced or blunted reactivity upon exposure to a challenge or salient stimulus, such as stress or ethanol‐associated cues. In addition, it may be the case that evaluation of ΔFosB expression would reveal long‐lasting cellular adaptations to ethanol dependence and relapse drinking, 34,72,73 which may not be reflected in c‐Fos expression due to potential habituation of this immediate early gene. Future studies may explore these possibilities and may also investigate the specific cell phenotypes associated with the observed c‐Fos changes in different brain areas as well as the necessity of c‐Fos‐expressing neurons to drinking behavior using activity‐dependent ablation of neuronal ensembles 52,74 .…”

Adolescent Alcohol Drinking Renders Adult Drinking BLA-Dependent: BLA Hyper-Activity as Contributor to Comorbid Alcohol Use Disorder and Anxiety Disorders

“…Voluntary alcohol drinking in adolescence, as opposed to adulthood, results in higher ΔFosB expression in the BLA [ 89 ]. ΔFosB is a transcription factor associated with drug-induced neural plasticity [ 90 ] and has been suggested as a neural marker for vulnerability to alcohol use disorder [ 89 , 91 ]. Overall, these findings suggest that alcohol drinking affects BLA function in a manner that would ultimately lead to hyper-activity or an increased BLA output.…”

Involvement of Centrally Projecting Edinger–Westphal Nucleus Neuropeptides in Actions of Addictive Drugs

“…Indeed, an increase in c-Fos expression in the EWcp has been observed following a 2 h limited access period [29]. Additionally, increased levels of FosB were observed in the EWcp after seven days of 24 h access to EtOH in prairie voles [30,31] and mice [23,32].…”