Activation of inflammatory signaling by lipopolysaccharide produces a prolonged increase of voluntary alcohol intake in mice

Abstract

Previous studies showed that mice with genetic predisposition for high alcohol consumption as well as human alcoholics show changes in brain expression of genes related to immune signaling. In addition, mutant mice lacking genes related to immune function show decreased alcohol consumption (Blednov et al., in press), suggesting that immune signaling promotes alcohol consumption. To test the possibility that activation of immune signaling will increase alcohol consumption, we treated mice with lipopolysaccaride (LPS; 1 mg/kg, i.p.) and tested alcohol consumption in the continuous two-bottle choice test. To take advantage of the long-lasting activation of brain immune signaling by LPS, we measured drinking beginning one week or one month after LPS treatment and continued the studies for several months. LPS produced persistent increases in alcohol consumption in C57/Bl6 J (B6) inbred mice, FVBxB6F1 and B6xNZBF1 hybrid mice, but not in FVB inbred mice. To determine if this effect of LPS is mediated through binding to TLR4, we tested mice lacking CD14, a key component of TLR4 signaling. These null mutants showed no increase of alcohol intake after treatment with LPS. LPS treatment decreased ethanol-conditioned taste aversion but did not alter ethanol-conditioned place preference (B6xNZBF1 mice). Electro-physiological studies of dopamine neurons in the ventral tegmental area showed that pretreatment of mice with LPS decreased the neuronal firing rate. These results suggest that activation of immune signaling promotes alcohol consumption and alters certain aspects of alcohol reward/aversion.

Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice

“…In light of these studies, it is likely that the aversion seen in the present study is driven by a decreased firing rate of midbrain dopaminergic neurons. In line with this evidence, LPS injection leads to a persistent reduction in the firing rate of dopaminergic cells (37). A decrease in firing rate of dopaminergic cells is sufficient to cause aversion, as demonstrated with optogenetic manipulation (38,39).…”

Cellular and behavioral effects of lipopolysaccharide treatment are dependent upon neurokinin-1 receptor activation

“…In addition to this anhedonia effect, LPS exposure has been shown to influence other behaviors of interest including sensitivity to painful stimuli [41], alcohol intake [42], and anxiety [43,44]. Future studies will examine the role of the NK1R in additional LPS-induced behaviors.…”

Immunophyllin Ligands Show Differential Effects on Alcohol Self-Administration in C57BL Mice

“…As an immunosuppressant, CsA has been postulated to block interleukin-2 transcription and translation as well as suppression of immune interferon-␥ growth factor, resulting in a decrease in interleukin-1, leading to the blockade of lymphocyte activation (Almawi and Melemedjian, 2000;Maramattom and Wijdicks, 2004). Recent studies (Blednov et al, 2011) show that immune signaling may promote alcohol consumption, and it is possible that the administration of these immunosuppressants could suppress the abnormal brain immune signaling to reduce alcohol consumption. Whether the alcohol preference change found here relates to Fig.…”