Modulation of Binge-like Ethanol Consumption by IL-10 Signaling in the Basolateral Amygdala

Abstract

Excessive ethanol consumption alters the neuroimmune system and particularly impacts the cytokine milieu of the CNS. Cytokine dysregulation has been shown to underlie addictive-like behaviors including alcohol abuse; however, many studies focus primarily on the proinflammatory cytokine profile and alcohol dependence. The current study furthers this research by determining the impact of excessive ethanol consumption on interleukin-10 (IL-10) and interleukin-4 (IL-4) activity in a model of non-dependent binge consumption called the “drinking in the dark” (DID) paradigm. Furthermore, the ability of IL-10 to modulate ethanol consumption was tested using site-directed pharmacology. Immunohistochemistry analyses determined that ethanol decreased IL-10 by 50% in the basolateral amygdala (BLA) but had no effect on IL-4. Neither IL-10 nor IL-4 were altered seen in the central amygdala (CEA). Enzyme linked immunosorbent assays confirmed that IL-10 was decreased in the amygdala but not in the serum, suggesting changes of this cytokine with the DID paradigm is restricted to the central nervous system. Finally, bilateral infusions of IL-10 into the BLA, but not CeA, reduced binge-like drinking and corresponding blood ethanol concentrations without impacting either locomotor activity or anxiety-like behavioral correlates. Together, these data support the idea that alcohol abuse dysregulates specific anti-inflammatory cytokines; however, ameliorating alcohol-induced effects on cytokines, like IL-10, may prove to be an effective therapy in curbing excessive consumption.

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

“…Interestingly, this is consistent with studies finding innate immune signaling contributes to the development of AUD (Crews et al., 2017; de Timary et al., 2017). Innate immune signaling cytokines alter EtOH consumption (Marshall et al., 2017, 2017), and cytokine receptors contribute to stress‐induced EtOH consumption (Karlsson et al., 2017). Further, immune signaling molecules are increased in postmortem human alcoholic brain (Crews et al., 2017) and regulate preference for alcohol drinking in animal studies (Mayfield et al., 2013).…”

“…However, reducing endotoxin release with antibiotics, probiotics, and drugs resulted in a loss of the stress hormone response, suggesting stress‐induced changes in blood endotoxin contribute to stress hormone responses (Ait‐Belgnaoui et al., 2012). Innate immune signaling cytokines also alter EtOH consumption (Marshall et al., 2016, 2017), and the cytokine receptors IL1R1 and TNFR1 contribute to stress‐induced EtOH consumption (Karlsson et al., 2017), suggesting the neuroimmune system may contribute to addiction. Cytokines also enhance stressful emotional states following alcohol withdrawal (Breese et al., 2008).…”

The role of neuroimmune signaling in alcoholism

“…Regarding the binge/intoxication, multiple immune interventions have been found to regulate alcohol consumption. Injection of the IL-1 receptor antagonist or the anti-inflammatory cytokine IL-10 into the basolateral amygdala reduced alcohol self-administration (Marshall et al, 2016a; Marshall et al, 2016c). Furthermore, microglial-inhibiting compounds blocked conditioned place preference to cocaine, suggesting a role for the neuroimmune system in the subjective reward of drugs (Northcutt et al, 2015).…”

Role of MyD88 in IL-1β and Ethanol Modulation of GABAergic Transmission in the Central Amygdala

“…Most notably, genomic studies in mice [5], rats [6], and humans [3,7,8] have identified several members of the Toll-like receptors (TLR) and interleukin-1/interleukin18 (IL-1/IL-18) receptor pathways in AUD [9,10]. Moreover, pharmacological [11][12][13], viral [14,15], or transgenic [2,9,11,[16][17][18][19][20] manipulation of the innate immune system leads to alterations of the ethanol-related behaviors in rodents. Collectively, this growing literature on innate immune responses critically contributing to the neurobiology of AUD [21][22][23] suggests that these pathways have high potential as targets for the development of new AUD therapeutic strategies [16,[24][25][26].…”