Summary: A new mouse study found that blocking a specific brain immune response reduces the drive to drink alcohol at night. The findings reveal a time-of-day interaction between the brain’s innate immune system and alcohol-motivated behaviour.
Source: University of Adelaide
University of Adelaide researchers identify a link between the brain’s immune signalling and evening alcohol intake
Researchers at the University of Adelaide report that inhibiting a particular immune receptor in the brain markedly lowered alcohol consumption in mice during their active (night) phase. The study, published in the journal Brain, Behavior and Immunity, demonstrates a time-dependent relationship between innate immune signalling and alcohol-related reward, pointing to new directions for understanding the biology behind alcohol use.
Lead author Jon Jacobsen, a PhD student in the University of Adelaide’s Discipline of Pharmacology, explains: “Alcohol is the most widely used psychoactive substance worldwide. To address harmful drinking and its consequences, we need better insight into the biological mechanisms that drive the motivation to drink. Circadian rhythms shape reward signalling in the brain, and reward responses to drug-related behaviour often peak during the evening. We investigated whether the brain’s immune system contributes to that peak and whether it could be turned off.”
The team focused on Toll-like receptor 4 (TLR4), an innate immune receptor expressed in the brain. They treated mice with (+)-Naltrexone, a compound known to antagonize TLR4, and measured alcohol preference and seeking across light and dark cycles.
When mice received (+)-Naltrexone, their alcohol drinking and preference declined significantly during the dark phase—the period when rodents normally show the strongest reward-related responses. “Blocking this specific component of the brain’s immune response substantially reduced the mice’s motivation to drink alcohol in the evening,” Jacobsen said.
Senior author Professor Mark Hutchinson, Director of the ARC Centre of Excellence for Nanoscale BioPhotonics and head of the Neuroimmunopharmacology laboratory, emphasized the broader implications: “These results support a growing body of evidence that the brain’s immune system influences drug-related reward. Given the prevalence of alcohol use and related harms in many countries, including Australia, further research is warranted to explore how immune targets might inform prevention or treatment strategies.”
Funding: This research was supported by the Australian Research Council (ARC), the US National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism.
Source institution: University of Adelaide
Journal: Brain, Behavior and Immunity (article published online August 30, 2017)
Key findings and scientific context
• Circadian influence on reward: The study confirms that alcohol-associated reward behaviour in mice is stronger during the dark (active) phase, aligning with known circadian modulation of reward circuits.
• Immune signalling and alcohol reward: Gene expression related to reward, thirst and immune responses rose during the dark cycle. Blocking TLR4 with (+)-Naltrexone reduced immune-related gene expression and lowered alcohol preference most markedly at night.
• Off-target effects and nuance: The authors observed that (+)-Naltrexone also reduced intake of non-alcoholic sweet solutions (saccharin), a side effect likely linked to decreases in tyrosine hydroxylase (Th) mRNA. This indicates TLR4 antagonism can influence broader reward-related pathways and highlights the need to evaluate specificity and potential unintended consequences.
• Overall implication: The data reveal a time-of-day dependent role for TLR4 in natural and alcohol-related reward behaviours in mice. These results suggest the brain’s innate immune signalling contributes to the motivation to drink and that immune-targeted approaches may have differential efficacy depending on circadian phase.
Original research article
Title: “The efficacy of (+)-Naltrexone on alcohol preference and seeking behaviour is dependent on light-cycle” by Jonathan Henry W. Jacobsen, Femke T.A. Buisman-Pijlman, Sanam Mustafa, Kenner C. Rice, and Mark R. Hutchinson. The paper reports experimental evidence linking TLR4 antagonism to reduced alcohol-seeking behaviour in mice, with strongest effects during the dark cycle.