Alcohol intake in two different mouse drinking models after recovery from the lipopolysaccharide-induced sickness reaction

Abstract

Neuroinflammation may play an important role in the development of alcohol addiction. Recent preclinical reports suggest that enhanced innate immune system signaling increases consumption of alcohol. Our aim was to study whether consequences of lipopolysaccharide (LPS)-induced sickness reaction increase long-term alcohol intake. Adult male C57BL/6J mice, housed in individually ventilated cages, were injected with LPS intraperitoneally (i.p.) and allowed to recover from an acute sickness reaction for 1 week before analysis of their alcohol intake in two different drinking models. Effects of LPS challenge were tested in a continuous two-bottle free choice test with increasing concentrations of alcohol and in a drinking in the dark (DID) binge model. In addition, the effect of repeatedly administered LPS during abstinence periods between binge drinking was analyzed in the DID model. In addition, the DID model was used to study the effects of the microglia inhibitor minocycline (50 mg/kg/day, 4 days) and purinergic P2X7 receptor antagonist Brilliant Blue G (75 mg/kg/day, 7 days) on alcohol intake. In contrast to previous findings, pretreatment with a 1-mg/kg dose of LPS did not significantly increase ethanol consumption in the continuous two-bottle choice test. As a novel finding, we report that increasing the LPS dose to 1.5 mg/kg reduced consumption of 18 and 21% (v/v) ethanol. In the DID model, pretreatment with LPS (0.2-1.5 mg/kg) did not significantly alter 15% or 20% ethanol consumption. Neither did repeated LPS injections affect binge alcohol drinking. Minocycline reduced alcohol, but also water, intake regardless of LPS pretreatment. No data on effects of P2X7 antagonists on alcohol consumption have been previously published; therefore, we report here that subchronic Brilliant Blue G had no effect on alcohol intake in the DID model. As a conclusion, further studies are needed to validate this LPS model of the interaction between immune system activation and alcohol consumption.

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

“…Pharmacological and genetic manipulations of neuroinflammatory targets have yielded promising results in reducing alcohol consumption across these different paradigms. For example, inhibition of microglia activation reduces alcohol consumption during the DID task in C57/BL6 male mice (Lainiola and Linden, 2017) and prevents relapse-like drinking in the 2BC task in male rats (Gajbhiye et al, 2018). Further, inhibition of microglial P2X7 receptor signaling also reduces alcohol consumption in C57/BL6 male mice during the DID paradigm (Lainiola and Linden, 2017).…”

Oleoylethanolamide, Neuroinflammation, and Alcohol Abuse

“…It is not clear enough and a focus of debate whether the alcohol-induced neuroinflammation would play a role in alcohol consumption. Some studies fail to detect a link between alcohol-induced neuroinflammation and drug consumption (Lainiola and Linden, 2017), and genetic and pharmacologic manipulation of TLR4 has been shown to have a minimal impact on rodent ethanol consumption (Harris et al, 2017). On the contrary, recent studies using anti-inflammatory mesenchymal stem cells suggest that targeting neuroinflammation could be an effective therapeutic approach to reduce alcohol consumption and relapse (Ezquer et al, 2018, 2017).…”

Toll-like receptor 3 activation increases voluntary alcohol intake in C57BL/6J male mice

“…However, despite evidence that TLR4/MyD88-dependent signaling is important for alcohol responses, it was recently found that TLR4 is not a critical determinant of excessive drinking in animal models (20,21). Moreover, a recent study could not replicate that LPS pretreatment increases alcohol consumption in continuous two-bottle-choice or drinking-in-the-dark (22). This suggests that other innate immune pathways may be important in the regulation of excessive alcohol consumption.…”