Sweeney Fabian F, O'Leary Olivia F, Cryan John F
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland.
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
Neuropharmacology. 2014 Jun;81:303-10. doi: 10.1016/j.neuropharm.2013.08.039. Epub 2013 Sep 17.
Although the underlying pathophysiology of anxiety disorders is unknown it is clear that a combination of genetic and environmental factors in early life predispose to disease risk. Preclinical research increasingly suggests an important role for the GABAB receptor in modulating anxiety behaviour, with GABAB receptor deficient mice having increased anxiety behaviour. Previous studies have highlighted critical windows during development where adult anxiety behaviour is primed. However, little is known regarding the role played by the GABAB receptors in the developmental processes that underlie adult anxiety behaviour. To this end, we treated male BALB/c mouse pups with the either the selective GABAB receptor agonist, R-baclofen (2 mg/kg, s.c), the GABAB receptor antagonist CGP 52432 (10 mg/kg and 30 mg/kg) or vehicle from postnatal days (P) 14-28. The anxiety behaviour of these mice was then assessed in adulthood (P62 onwards) in a battery of behavioural tests comprising; the stress induced hyperthermia (SIH) test, defensive marble burying (DMB), elevated-plus maze (EPM) and the forced swim test (FST). Postnatal R-baclofen treatment resulted in increased anxiety-like behaviour in the EPM as shown by approach-avoidance and ethological measures. Other behavioural measures were not significantly altered. Interestingly, blockade of GABAB receptors with CGP52432 in early life caused no alterations in emotional behaviour. These data suggest that during early life GABAB receptor signalling can play a functional role in programing anxiety behaviour in adulthood. The underlying neurodevelopmental processes underlying these effects remain to be discovered.
尽管焦虑症的潜在病理生理学尚不清楚，但很明显，早期生活中的遗传和环境因素共同作用会增加患病风险。临床前研究越来越多地表明，GABAB受体在调节焦虑行为中起重要作用，GABAB受体缺陷小鼠的焦虑行为增加。先前的研究强调了发育过程中的关键窗口期，成年焦虑行为在此期间被引发。然而，关于GABAB受体在成年焦虑行为背后的发育过程中所起的作用，我们知之甚少。为此，我们从出生后第14天至28天，用选择性GABAB受体激动剂R-巴氯芬（2mg/kg，皮下注射）、GABAB受体拮抗剂CGP 52432（10mg/kg和30mg/kg）或赋形剂处理雄性BALB/c小鼠幼崽。然后在成年期（出生后第62天及以后），通过一系列行为测试评估这些小鼠的焦虑行为，这些测试包括：应激诱导体温过高（SIH）测试、防御性埋球（DMB）、高架十字迷宫（EPM）和强迫游泳测试（FST）。出生后用R-巴氯芬治疗导致在EPM中出现类似焦虑的行为增加，这通过接近-回避和行为学测量得以体现。其他行为测量没有显著改变。有趣的是，在生命早期用CGP52432阻断GABAB受体并没有导致情绪行为的改变。这些数据表明，在生命早期，GABAB受体信号传导可以在成年期焦虑行为的编程中发挥功能性作用。这些效应背后的潜在神经发育过程仍有待发现。
