Region‐Specific Induction of FosB/ΔFosB by Voluntary Alcohol Intake: Effects of Naltrexone

Abstract

Background ΔFosB is the best characterized transcription factor induced by chronic stimulation. Although previous studies have demonstrated that chronic passive ethanol exposure alters ΔFosB immunoreactivity (IR), the effect of chronic voluntary ethanol consumption on ΔFosB remains unknown. Furthermore, although previous studies have demonstrated that the opioid antagonist naltrexone reduces alcohol consumption in clinical and pre-clinical settings, the effect of naltrexone on FosB/ΔFosB has not been explored. Here we examined the effects of chronic voluntary ethanol intake and naltrexone on FosB/ΔFosB IR in striatal region and prefrontal cortex, and the effect of naltrexone on voluntary ethanol intake. Methods We utilized immunohistochemistry to define the changes in FosB/ΔFosB IR induced by chronic voluntary ethanol intake under a two-bottle intermittent access of 20% ethanol model and by systematic administration (intraperitoneal injection) of naltrexone in Sprague-Dawley rats. Results Chronic (15 drinking sessions in 35 days) voluntary ethanol intake robustly induces FosB/ΔFosB IR in nucleus accumbens core, dorsolateral striatum and orbitofrontal cortex, but not in nucleus accumbens shell, dorsomedial striatum and medial prefrontal cortex. Systemic administration of naltrexone for six days significantly reduced voluntary ethanol consumption and FosB/ΔFosB IR induced by chronic voluntary ethanol intake. Conclusion Our results suggest that chronic voluntary ethanol intake induces FosB/ΔFosB IR in a sub-region-specific manner and which involves activation of endogenous opioid system.

Ablation of μ opioid receptor-expressing GABA neurons in rostromedial tegmental nucleus increases ethanol consumption and regulates ethanol-related behaviors

“…Thirty-three of the 36 rats (91.6%) under the I2BC paradigm significantly escalated their ethanol consumption (data not shown) and maintained it at a stable level 6–8 weeks into the drinking program, in agreement with our previous report (Li et al, 2010). Three rats drank less than 3 g/kg of ethanol in 24 hours and were excluded from further study.…”

Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse

“…Taken together, these characteristics suggest that IA2BC training is useful to model escalation to excessive drinking, as well as for binge drinking, in the rat. Importantly, the model shows three aspects of validity: face validity , given the similarity to the drinking pattern of human alcoholics (Koob, 2003; Koob & Volkow, 2010; Vengeliene, Bilbao, Molander, & Spanagel, 2008); construct validity , given the high correlation of BEC and alcohol intake levels, and the neuroadaptations found following IA2BC training; and predictive validity , given the accumulating findings in the literature reporting that drugs approved by the US Food and Drug Administration for the treatment of alcoholism (i.e., naltrexone and acamprosate) suppress alcohol intake in this model (e.g., Li et al, 2010; Sabino et al, 2013; Simms et al, 2008). …”

Cocaine reverses the naltrexone-induced reduction in operant ethanol self-administration: The effects on immediate-early gene expression in the rat prefrontal cortex

“…We focused on the prefrontal cortex because of its contribution to addictive behaviour (Lüscher and Malenka, 2011), its involvement in compulsive ethanol drinking, its demonstrated sensitivity to naltrexone and acamprosate treatment (Burattini et al, 2008;Li et al, 2010;Yu et al, 2011), and its critical role in integrating and regulating cognitive behaviour in rodents and in humans (e.g., Abernathy et al, 2010;Dayas et al, 2007;Vengeliene et al, 2009). …”