Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, South Australia, Australia.
Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, South Australia, Australia.
Neuropharmacology. 2018 Jan;128:460-473. doi: 10.1016/j.neuropharm.2017.09.028. Epub 2017 Sep 22.
Adolescents frequently engage in risky behaviours such as binge drinking. Binge drinking, in turn, perturbs neurodevelopment reinforcing reward seeking behaviour in adulthood. Current animal models are limited in their portrayal of this behaviour and the assessment of neuroimmune involvement (specifically the role of Toll-like receptor 4 (TLR4)). Therefore, the aims of this project were to develop a more relevant animal model of adolescent alcohol exposure and to characterise its effects on TLR4 signalling and alcohol-related behaviours later life. Balb/c mice received a short (P22-P25), low dose alcohol binge during in early adolescence, and underwent tests to investigate anxiety (elevated plus maze), alcohol seeking (conditioned place preference) and binge drinking behaviour (drinking in the dark) in adulthood. Four doses of alcohol during adolescence increased alcohol-induced conditioned place preference and alcohol intake in adulthood. However, this model did not affect basal elevated plus maze performance. Subsequent analysis of nucleus accumbal mRNA, revealed increased expression of TLR4-related mRNAs in mice who received alcohol during adolescence. To further elucidate the role of TLR4, (+)-Naltrexone, a biased TLR4 antagonist was administered 30 min before or after the adolescent binge paradigm. When tested in adulthood, (+)-Naltrexone treated mice exhibited reduced alcohol intake however, alcohol seeking and anxiety behaviour was unaltered. This study highlights that even a small amount of alcohol, when given during a critical neurodevelopmental period, can potentiate alcohol-related behaviours and TLR4 activation later in life. Interestingly, attenuation of TLR4 before or after adolescent alcohol exposure reduced only binge alcohol intake in adulthood.
青少年经常从事冒险行为，如狂饮。狂饮反过来又扰乱了神经发育，增强了成年后的奖励寻求行为。目前的动物模型在描述这种行为和评估神经免疫参与（特别是 Toll 样受体 4（TLR4）的作用）方面存在局限性。因此，本项目的目的是开发一种更相关的青少年酒精暴露动物模型，并描述其对 TLR4 信号转导和成年后与酒精相关行为的影响。Balb/c 小鼠在青春期早期接受短暂（P22-P25）、低剂量的酒精 binge，然后进行测试，以调查成年后的焦虑（高架十字迷宫）、酒精寻求（条件性位置偏好）和 binge 饮酒行为（黑暗中饮酒）。青春期期间给予四剂酒精会增加酒精诱导的条件性位置偏好和成年后的酒精摄入量。然而，这种模型不会影响基础高架十字迷宫性能。随后对伏隔核 mRNA 的分析显示，在青春期接受酒精的小鼠中，TLR4 相关 mRNAs 的表达增加。为了进一步阐明 TLR4 的作用，在青春期 binge 范式之前或之后 30 分钟给予（+）-纳曲酮，一种偏向性 TLR4 拮抗剂。在成年期进行测试时，（+）-纳曲酮处理的小鼠表现出减少的酒精摄入量，然而，酒精寻求和焦虑行为没有改变。这项研究强调，即使是少量的酒精，在关键的神经发育时期给予，也可以增强成年后与酒精相关的行为和 TLR4 激活。有趣的是，在青春期酒精暴露之前或之后抑制 TLR4 仅减少了成年期 binge 酒精的摄入量。
