Department of Psychiatry, Division of Molecular Psychiatry, Ribicoff Research Facilities, Yale University School of Medicine, 34 Park St, New Haven, CT 06508, USA.
Psychopharmacology (Berl). 2013 Feb;225(3):569-77. doi: 10.1007/s00213-012-2844-4. Epub 2012 Sep 15.
Repeated or prolonged exposure to stress has profound effects on a wide spectrum of behavioral and neurobiological processes and has been associated with the pathophysiology of depression. The multifaceted nature of this disorder includes despair, anhedonia, diminished motivation, and disrupted cognition, and it has been proposed that depression is also associated with reduced reward-motivated learning. We have previously reported that prior chronic corticosterone exposure to mice produces a lasting depressive-like state that can be reversed by chronic antidepressant treatment.
In the present study, we tested the effects of prior chronic exposure to corticosterone (50 μg/ml) administered to rats or to mice in drinking water for 14 days followed by dose-tapering over 9 days.
The exposure to corticosterone produced lasting deficits in the acquisition of reward-related learning tested on a food-motivated instrumental task conducted 10-20 days after the last day of full dose corticosterone exposure. Rats exposed to corticosterone also displayed reduced responding on a progressive ratio schedule of reinforcement when tested on day 21 after exposure. Amitriptyline (200 mg/ml in drinking water) exposure for 14 days to mice produced the opposite effect, enhancing food-motivated instrumental acquisition and performance. Repeated treatment with amitriptyline (5 mg/kg, intraperitoneally; bid) subsequent to corticosterone exposure also prevented the corticosterone-induced deficits in rats.
These results are consistent with aberrant reward-related learning and motivational processes in depressive states and provide new evidence that stress-induced neuroadaptive alterations in cortico-limbic-striatal brain circuits involved in learning and motivation may play a critical role in aspects of mood disorders.
反复或长期暴露于压力会对广泛的行为和神经生物学过程产生深远影响，并与抑郁症的病理生理学有关。这种疾病的多方面性质包括绝望、快感缺失、动机减弱和认知障碍，有人提出抑郁症也与奖励动机学习减少有关。我们之前报道过，先前给小鼠慢性暴露于皮质酮（50μg/ml）会产生持久的抑郁样状态，这种状态可以通过慢性抗抑郁治疗来逆转。
在本研究中，我们测试了先前给大鼠或小鼠在饮用水中连续 14 天暴露于皮质酮（50μg/ml），然后在 9 天内逐渐减少剂量，对其产生的影响。
暴露于皮质酮会导致在进行食物动机性仪器任务时，对奖励相关学习的获得产生持久的缺陷，该任务在最后一天完全暴露于皮质酮后 10-20 天进行。暴露于皮质酮的大鼠在暴露后第 21 天进行递增比率强化程序测试时，反应也减少了。连续 14 天给小鼠服用阿米替林（200mg/ml 在饮用水中）产生了相反的效果，增强了食物动机性仪器的获取和表现。随后在皮质酮暴露后，重复给予阿米替林（5mg/kg，腹膜内；bid）治疗也能防止皮质酮引起的大鼠缺陷。
这些结果与抑郁状态下异常的奖励相关学习和动机过程一致，并提供了新的证据，表明与学习和动机相关的皮质-边缘-纹状体大脑回路中应激诱导的神经适应性改变可能在情绪障碍的某些方面发挥关键作用。
