Mohammadi Sarasa A, Burton Thomas J, Christie MacDonald J
Discipline of Pharmacology, The University of Sydney, Sydney, NSW 2006, Australia.
Animal Behavioural Facility, Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia.
Behav Brain Res. 2017 Jun 15;328:105-114. doi: 10.1016/j.bbr.2017.04.005. Epub 2017 Apr 10.
The α9α10-subtype of nicotinic acetylcholine receptor (nAChR) has recently garnered interest in biomedicine and is being pursued as an analgesic target. However, the receptor exhibits diverse tissue distribution, the function of which is known to varying degrees, and targeting this receptor for clinical treatments without a broad understanding of its function may have adverse consequences. The α9α10-nAChR is expressed in the adrenal and pituitary glands, suggesting a potential role in the stress response, but little is known about its function in this tissue. Here we determined a role for the α9α10-nAChR in behavioural and physiological stress responses, by comparing the stress- and affect-related phenotypes of wildtype and α9-nAChR knockout mice. Naïve knockout mice exhibited largely normal behaviour on standard tests of affective behaviour. However, after sub-chronic restraint stress knockout mice showed significantly decreased stress-induced arousal and increased anxiety-like behaviour when compared to wildtype animals. Physiologically, corticosterone responses were muted in knockout mice after an acute stressor, but exaggerated in response to the same stressor after undergoing sub-chronic stress. Behavioural profiling of the α9-nAChR knockout mice in the home-cage revealed that circadian patterns of activity were altered when compared to wildtype controls. Furthermore, knockout mice showed altered responses to a period of reward discounting, resulting in anhedonia-like behaviour in a sucrose preference test where WT mice continued to seek reward. These experiments uncover a novel role for the α9α10-nAChR in mounting a normal stress response and in the regulation of affective- and reward-related behaviour, and suggest that pursuing the receptor for clinical treatments may not be as straightforward as has been suggested.
烟碱型乙酰胆碱受体（nAChR）的α9α10亚型最近在生物医学领域引起了关注，并被作为一个镇痛靶点进行研究。然而，该受体表现出多样的组织分布，其功能在不同程度上为人所知，在对其功能缺乏广泛了解的情况下将该受体作为临床治疗靶点可能会产生不良后果。α9α10-nAChR在肾上腺和垂体中表达，提示其在应激反应中可能发挥作用，但对其在该组织中的功能了解甚少。在此，我们通过比较野生型和α9-nAChR基因敲除小鼠的应激和情感相关表型，确定了α9α10-nAChR在行为和生理应激反应中的作用。未经处理的基因敲除小鼠在情感行为的标准测试中表现出基本正常的行为。然而，与野生型动物相比，亚慢性束缚应激后基因敲除小鼠的应激诱导觉醒显著降低，焦虑样行为增加。在生理方面，急性应激源作用后基因敲除小鼠的皮质酮反应减弱，但在经历亚慢性应激后对相同应激源的反应增强。对α9-nAChR基因敲除小鼠在饲养笼中的行为分析表明，与野生型对照相比，其昼夜活动模式发生了改变。此外，基因敲除小鼠对一段时间的奖励折扣反应改变，在蔗糖偏好试验中表现出快感缺失样行为，而野生型小鼠继续寻求奖励。这些实验揭示了α9α10-nAChR在产生正常应激反应以及调节情感和奖励相关行为方面的新作用，并表明将该受体用于临床治疗可能不像之前认为的那么简单。
