Combined Effects of Acamprosate and Escitalopram on Ethanol Consumption in Mice

Abstract

Background Major depression is one of the most prevalent psychiatry comorbidities of alcohol use disorders (AUD). Since negative emotions can trigger craving and increase the risk of relapse, treatments that target both conditions simultaneously may augment treatment success. Previous studies showed a potential synergist effect of FDA approved medication for AUD acamprosate and the antidepressant escitalopram. In this study, we investigated the effects of combining acamprosate and escitalopram on ethanol consumption in stress-induced depressed mice. Methods Forty singly-housed C57BL/6J male mice were subjected to chronic unpredictable stress. In parallel, 40 group-housed male mice were subjected to normal husbandry. After 3 weeks, depressive- and anxiety-like behaviors and ethanol consumption were assessed. For the next 7 days, mice were injected with saline, acamprosate (200 mg/kg; twice/day), escitalopram (5 mg/kg; twice/day), or their combination (n = 9–11/drug group/stress group). Two-bottle choice limited access drinking of 15% ethanol and tap water was performed 3 hours into dark phase for 2 hours immediately after the dark phase daily injection. Ethanol drinking was monitored for another 7 days without drug administration. Results Mice subjected to the chronic unpredictable stress paradigm for 3 weeks showed apparent depression- and anxiety-like behaviors compared to their non-stressed counterparts including longer immobility time in the forced swim test and lower sucrose preference. Stressed mice also displayed higher ethanol consumption and preference in a 2-bottle choice drinking test. During the drug administration period, the escitalopram-only and combined drug groups showed significant reduction in ethanol consumption in non-stressed mice, while only the combined drug group showed significantly reduced consumption in stressed mice. However, such reduction did not persist into the post-drug administration period. Conclusions The combination of acamprosate and escitalopram suppressed ethanol intake in both non-stressed and stressed mice, hence this combination is potentially helpful for AUD individuals with or without comorbid depression to reduce alcohol use.

High Drinking in the Dark (HDID) mice are sensitive to the effects of some clinically relevant drugs to reduce binge-like drinking

“…In a 2-bottle choice version of the 2 hr access DID test, male C57BL/6J mice showed no reductions in intake of 15% ethanol following repeated daily injections of 400 mg/kg acamprosate. Mice had previously been acclimated to the ethanol choice for 14 days, and lack of response was found regardless of whether or not the mice had been exposed to chronic unpredictable stress 32 .…”

Social and environmental enrichment has different effects on ethanol and sucrose consumption in mice

“…It should be noted that the model of sucrose consumption described in this study is different to the model of sucrose consumption commonly used for measuring depression-like behaviors. The later model generally involves administering lower concentrations of sucrose to mice for short periods (once weekly or for a few days at a time) (e.g., see Benturquia et al, 2007;Covington, Vialou, LaPlant, Ohnishi, & Nestler, 2011;Ho et al, 2016). However, the DID model generally uses higher sucrose concentrations which are administered for long periods of time (daily for weeks to months) (e.g., see Fritz et al, 2014;Gritz et al, 2016;Patkar et al, 2017).…”

Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression Comorbidity: The Role of Neurogenesis

“…Nonetheless, taking in mind that the evaluation of the effectiveness of conventional AD treatment should be done considering the delay in its therapeutic effects, studies should go beyond short-term evaluations, assessing long-term consequences of treatment in animal models that better mimic AUD patient conditions [109]. Thus, unlike studies using acute treatments, authors that evaluated chronic and subchronic escitalopram, sertraline, paroxetine, fluoxetine (SSRIs), and duloxetine, dual serotonin/norepinephrine reuptake inhibitor (SNRI) treatments found that, along the treatment period, animals showed lower alcohol intake levels, but cessation of treatment produced a restoration of basal alcohol consumption [110][111][112]. Ho et al [110] also found an augmentation in alcohol intake in depressed animals once treatment with escitalopram ceased.…”

“…Thus, unlike studies using acute treatments, authors that evaluated chronic and subchronic escitalopram, sertraline, paroxetine, fluoxetine (SSRIs), and duloxetine, dual serotonin/norepinephrine reuptake inhibitor (SNRI) treatments found that, along the treatment period, animals showed lower alcohol intake levels, but cessation of treatment produced a restoration of basal alcohol consumption [110][111][112]. Ho et al [110] also found an augmentation in alcohol intake in depressed animals once treatment with escitalopram ceased. Interestingly, authors also found the same effect in animals under combination of AD (escitalopram) and anti-relapse (acamprosate) treatments.…”