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Brain Behav Immun. 2018 Jan;67:181-193. doi: 10.1016/j.bbi.2017.08.021. Epub 2017 Aug 30.

The efficacy of (+)-Naltrexone on alcohol preference and seeking behaviour is dependent on light-cycle.

Author information

1
Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, South Australia, Australia.
2
Discipline of Physiology, Adelaide Medical School, University of Adelaide, South Australia, Australia; ARC Centre of Excellence for Nanoscale Biophotonics, University of Adelaide, South Australia, Australia.
3
Drug Design and Synthesis Section, NIDA, Rockville, MD, USA.
4
Discipline of Physiology, Adelaide Medical School, University of Adelaide, South Australia, Australia; ARC Centre of Excellence for Nanoscale Biophotonics, University of Adelaide, South Australia, Australia. Electronic address: mark.hutchinson@adelaide.edu.au.

Abstract

Circadian rhythm affects drug-induced reward behaviour and the innate immune system. Peaks in reward-associated behaviour and immune responses typically occur during the active (dark) phase of rodents. While the role of the immune system, specifically, Toll-like receptor 4 (TLR4, an innate immune receptor) in drug-induced reward is becoming increasingly appreciated, it is unclear whether its effects vary according to light-cycle. Therefore, the aim of this study was to characterise the effects of the phase of the light-cycle and the state of the innate immune system on alcohol reward behaviour and subsequently determine whether the efficacy of targeting the immune component of drug reward depends upon the light-cycle. This study demonstrates that mice exhibit greater alcohol-induced conditioned place preference and alcohol two-bottle choice preference during the dark cycle. This effect overlapped with elevations in reward-, thirst- and immune-related genes. Administration of (+)-Naltrexone, a TLR4 antagonist, reduced immune-related gene mRNA expression and alcohol preference with its effects most pronounced during the dark cycle. However, (+)-Naltrexone, like other TLR4 antagonists exhibited off-target side effects, with a significant reduction in overall saccharin intake - an effect likely attributable to a reduction in tyrosine hydroxylase (Th) mRNA expression levels. Collectively, the study highlights a link between a time-of-day dependent influence of TLR4 on natural and alcohol reward-like behaviour in mice.

KEYWORDS:

Alcohol; Circadian; Interferon; TRIF; Time-of-day; Toll-like receptor 4; Tyrosine hydroxylase

PMID:
28864261
DOI:
10.1016/j.bbi.2017.08.021
[Indexed for MEDLINE]

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