Bergamini Giorgio, Cathomas Flurin, Auer Sandra, Sigrist Hannes, Seifritz Erich, Patterson Michael, Gabriel Cecilia, Pryce Christopher R
Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Zurich, Switzerland.
Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
Eur Neuropsychopharmacol. 2016 Sep;26(9):1448-1464. doi: 10.1016/j.euroneuro.2016.06.009. Epub 2016 Jul 13.
A major domain of depression is decreased motivation for reward. Translational automated tests can be applied in humans and animals to study operant reward behaviour, aetio-pathophysiology underlying deficits therein, and effects of antidepressant treatment. Three inter-related experiments were conducted to investigate depression-relevant effects of chronic psychosocial stress on operant behaviour in mice. (A) Non-manipulated mice were trained on a complex reversal learning (CRL) test with sucrose reinforcement; relative to vehicle (VEH), acute antidepressant agomelatine (AGO, 25mg/kg p.o.) increased reversals. (B) Mice underwent chronic social defeat (CSD) or control handling (CON) on days 1-15, and were administered AGO or VEH on days 10-22. In a progressive ratio schedule motivation test for sucrose on day 15, CSD mice made fewer responses; AGO tended to reverse this effect. In a CRL test on day 22, CSD mice completed fewer reversals; AGO tended to increase reversals in CSD mice associated with an adaptive increase in perseveration. (C) Mice with continuous operant access to water and saccharin solution in the home cage were exposed to CSD or CON; CSD mice made fewer responses for saccharin and water and drank less saccharin in the active period, and drank more water in the inactive period. In a separate CSD cohort, repeated AGO was without effect on these home cage operant and consummatory changes. Overall, this study demonstrates that psychosocial stress in mice leads to depression-relevant decreases in motivation and cognition in operant reward tests; partial reversal of these deficits by AGO provides evidence for predictive validity.
抑郁症的一个主要领域是奖励动机降低。转化自动化测试可应用于人类和动物，以研究操作性奖励行为、其中潜在缺陷的病因病理生理学以及抗抑郁治疗的效果。进行了三项相互关联的实验，以研究慢性心理社会应激对小鼠操作性行为的抑郁症相关影响。（A）未处理的小鼠在蔗糖强化的复杂逆向学习（CRL）测试中接受训练；相对于载体（VEH），急性抗抑郁药阿戈美拉汀（AGO，25mg/kg口服）增加了逆向次数。（B）小鼠在第1 - 15天接受慢性社会挫败（CSD）或对照处理（CON），并在第10 - 22天给予AGO或VEH。在第15天对蔗糖的渐进比率时间表动机测试中，CSD小鼠的反应较少；AGO倾向于逆转这种效果。在第22天的CRL测试中，CSD小鼠完成的逆向次数较少；AGO倾向于增加CSD小鼠的逆向次数，这与持续性的适应性增加有关。（C）在家笼中持续操作性获取水和糖精溶液的小鼠暴露于CSD或CON；CSD小鼠对糖精和水的反应较少，在活跃期饮用的糖精较少，在非活跃期饮用的水较多。在一个单独的CSD队列中，重复给予AGO对这些家笼操作性和消费性变化没有影响。总体而言，本研究表明，小鼠的心理社会应激会导致操作性奖励测试中与抑郁症相关的动机和认知下降；AGO对这些缺陷的部分逆转提供了预测有效性的证据。
