Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Hosur Road, PB # 2900, Bangalore, 560 029, India.
Psychopharmacology (Berl). 2011 Sep;217(2):239-53. doi: 10.1007/s00213-011-2279-3. Epub 2011 Apr 16.
Chronic stress results in cognitive impairment, affects hippocampal neurogenesis and is known to precipitate affective disorders such as depression. In addition to stress, neurotransmitters such as acetylcholine (ACh) modulate adult neurogenesis. Earlier, we have shown that oxotremorine, a cholinergic muscarinic agonist, ameliorates stress-induced cognitive impairment and restores cholinergic function.
In the current study, we have looked into the possible involvement of adult neurogenesis in cognitive restoration by oxotremorine. Further, we have assessed the effect of oxotremorine treatment on depression-like behaviour and hippocampal volumes in stressed animals.
Chronic restraint stressed rats were treated with either vehicle or oxotremorine. For neurogenesis studies, proliferation, survival and differentiation of the progenitor cells in the hippocampus were examined using 5'-bromo-2-deoxyuridine immunohistochemistry. Depression-like behaviour was evaluated using forced swim test (FST) and sucrose consumption test (SCT). Volumes were estimated using Cavalieri's estimator.
Hippocampal neurogenesis was severely decreased in stressed rats. Ten days of oxotremorine treatment to stressed animals partially restored proliferation and survival, while it completely restored the differentiation of the newly formed cells. Stressed rats showed increased immobility and decreased sucrose preference in the FST and SCT, respectively, and oxotremorine ameliorated this depression-like behaviour. In addition, oxotremorine treatment recovered the stress-induced decrease in hippocampal volume.
These results indicate that the restoration of impaired neurogenesis and hippocampal volume could be associated with the behavioural recovery by oxotremorine. Our results imply the muscarinic regulation of adult neurogenesis and incite the potential utility of cholinomimetics in ameliorating cognitive dysfunction in stress-related disorders.
慢性应激导致认知障碍，影响海马神经发生，并已知会引发抑郁等情感障碍。除了应激之外，神经递质，如乙酰胆碱（ACh），调节成年神经发生。我们之前已经表明，拟副交感神经药氧托溴铵，一种胆碱能毒蕈碱激动剂，可改善应激引起的认知障碍并恢复胆碱能功能。
在目前的研究中，我们研究了氧托溴铵对认知恢复的可能涉及的成年神经发生。此外，我们评估了氧托溴铵治疗对应激动物的抑郁样行为和海马体积的影响。
慢性束缚应激大鼠用载体或氧托溴铵处理。为了进行神经发生研究，使用 5'-溴-2-脱氧尿苷免疫组织化学法检查海马中的祖细胞的增殖、存活和分化。使用强迫游泳试验（FST）和蔗糖消耗试验（SCT）评估抑郁样行为。使用 Cavalieri 的估计器估计体积。
应激大鼠的海马神经发生严重减少。应激动物的 10 天氧托溴铵治疗部分恢复了增殖和存活，而完全恢复了新形成细胞的分化。应激大鼠在 FST 和 SCT 中分别表现出增加的不动性和减少的蔗糖偏好，而氧托溴铵改善了这种抑郁样行为。此外，氧托溴铵治疗恢复了应激引起的海马体积减少。
这些结果表明，受损神经发生和海马体积的恢复可能与氧托溴铵的行为恢复有关。我们的结果表明，成年神经发生的毒蕈碱调节，并激发了拟胆碱能药物在改善应激相关障碍中的认知功能障碍的潜在效用。
