Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by alpha1-adrenergic receptors in medial prefrontal cortex.
Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by alpha1-adrenergic receptors in medial prefrontal cortex.
复制标题
DOI：
10.1016/j.pnpbp.2010.04.016
复制
发表时间：
2010-08-16
影响因子：
5.6
通讯作者：
Morilak, David A.
中科院分区：
文献类型：
--
作者：
Bondi, Corina O.;Jett, Julianne D.;Morilak, David A.
慢性压力是许多精神病理状况的危险因素，包括抑郁症和焦虑症。与前额叶皮质功能障碍相关的认知障碍是这类疾病的主要组成部分。使用注意定势转换测试（AST），我们先前已经表明，提高大鼠内侧前额叶皮层（mPFC）的去甲肾上腺素能活性可以促进认知定势转换，以及慢性不可预测的压力（CUS）引起的定势转换缺陷。目前尚不清楚，但是，如果去甲肾上腺素能调节功能受到慢性应激，也许有助于应激诱导的认知缺陷。因此，第一项研究调查了急性升高mPFC中的去甲肾上腺素能活性是否仍能增强慢性应激后的认知功能。如前所述，CUS损害了AST上的认知定势转换。急性全身给予α2-肾上腺素能自身受体拮抗剂阿替美唑可消除这种缺陷。微透析显示，在基线或行为测试期间，暴露于DMSO和未应激对照大鼠的mPFC中细胞外去甲肾上腺素（NE）水平无差异，阿替美唑后增加幅度相当。在第二个实验中，通过行为测试在CUS治疗期间用选择性NE再摄取阻断剂地昔帕明长期治疗大鼠。同样，CUS损害了车辆治疗大鼠的认知定势转移，慢性地昔帕明治疗防止了这种缺陷。在测试之前，急性阻断mPFC中的突触后α1-肾上腺素能受体阻断了地昔帕明对认知定势转换的有益作用。这些结果表明，地昔帕明通过激活mPFC中的α1-肾上腺素能受体来恢复已被慢性应激损害的认知定势转换能力。因此，去甲肾上腺素能调节mPFC的能力在CUS后保持完整，这代表了一种可能的底物，抗抑郁药可以通过这种底物在抑郁症的治疗中发挥其有益的作用。
Chronic stress is a risk factor for many psychopathological conditions, including depression and anxiety disorders. Cognitive impairments associated with prefrontal cortical dysfunction are a major component of such illnesses. Using an attentional set shifting test (AST), we have previously shown that elevating noradrenergic activity in rat medial prefrontal cortex (mPFC) can facilitate cognitive set-shifting, and that chronic unpredictable stress (CUS) caused set-shifting deficits. It is not known, however, if noradrenergic modulatory function is compromised by chronic stress, perhaps contributing to the stress-induced cognitive deficit. Thus, the first study investigated whether acutely elevating noradrenergic activity in mPFC still enhances cognitive function after chronic stress. As previously demonstrated, CUS impaired cognitive set-shifting on the AST. This deficit was abolished by acute systemic administration of the α2-adrenergic autoreceptor antagonist, atipamezole. Microdialysis revealed no differences in extracellular norepinephrine (NE) levels in mPFC of CUS-exposed and unstressed control rats at baseline or during behavioral testing, and comparable increases after atipamezole. In the second experiment, rats were treated chronically with the selective NE reuptake blocker, desipramine, during the CUS treatment through behavioral testing. Again, CUS impaired cognitive set-shifting in vehicle-treated rats, and chronic desipramine treatment prevented such deficits. Acute blockade of post-synaptic α1-adrenergic receptors in mPFC prior to testing blocked the beneficial effect of desipramine on cognitive set-shifting. These results suggest that desipramine restores cognitive set-shifting capability that has been compromised by chronic stress by activating α1-adrenergic receptors in the mPFC. Thus, noradrenergic modulatory capability in mPFC remains intact after CUS, and this represents one possible substrate by which antidepressants may exert their beneficial effects in the treatment of depression.
登录
查看更多内容
影响因子：
11
作者：
Bessa, J. M.;Ferreira, D.;Sousa, N.
通讯作者：
Sousa, N.
影响因子：
10.6
作者：
Aston-Jones, G;Rajkowski, J;Cohen, J
通讯作者：
Cohen, J
影响因子：
11.3
作者：
Fossati, P;Amar, G;Allilaire, JF
通讯作者：
Allilaire, JF
影响因子：
3.7
作者：
Clarke, H. F.;Walker, S. C.;Roberts, A. C.
通讯作者：
Roberts, A. C.
影响因子：
1.9
作者：
BUNSEY, MD;STRUPP, BJ
通讯作者：
STRUPP, BJ