Desipramine attenuates working memory impairments induced by partial loss of catecholamines in the rat medial prefrontal cortex
Desipramine attenuates working memory impairments induced by partial loss of catecholamines in the rat medial prefrontal cortex
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DOI：
10.1007/s00213-005-0221-2
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发表时间：
2006-01-01
影响因子：
3.4
通讯作者：
Finlay, JM
中科院分区：
文献类型：
--
作者：
Clinton, SM;Sucharski, IL;Finlay, JM
精神分裂症受试者前额叶皮质中酪氨酸羟化酶免疫反应(TH-IR)轴突的密度在皮质深层可减少50%(Am J Pechiatry 156：1580-1589,1999)。在此之前，我们证明了类似于60%的大鼠内侧前额叶皮质(MPFC)TH-IR轴突的丢失降低了局部基础和应激诱发的细胞外多巴胺(DA)浓度，这表明mPFC中适度的DA轴突的丢失足以改变剩余DA神经元的神经化学活动(NeuroScience 93：497-505,1999)。为了进一步评估部分mPFC DA耗竭的功能后果，我们在T迷宫延迟反应任务中观察了大鼠mPFC的6-羟基多巴胺损伤对行为的影响。我们还评估了慢性给予去甲肾上腺素(NE)摄取抑制剂地昔帕明(DMI)是否能减轻病变诱导的T迷宫操作缺陷。先前的研究表明，抑制mPFC的NE转运导致细胞外DA和NE的增加。适度的mPFC DA和NE的丢失(分别相当于50%和10%的损失)足以损害延迟反应行为，部分原因是持续性反应的增加。慢性DMI治疗(3 mg/kg渗透压泵给药)降低了对照组大鼠的行为表现，但减轻了先前遭受mPFC DA和NE丢失的大鼠的延迟反应行为缺陷(分别类似于75%和35%的丢失)。这些数据表明，前额叶皮质DA和NE的适度丢失足以损害认知功能，这些行为影响可以通过抑制NE转运体来减弱。
The density of tyrosine hydroxylase-immunoreactive (TH-IR) axons in the prefrontal cortex of schizophrenic subjects may be reduced by as much as 50% in the deep cortical layers (Am J Psychiatry 156:1580-1589, 1999). Previously, we demonstrated that similar to 60% loss of TH-IR axons in the rat medial prefrontal cortex (mPFC) decreases local basal and stress-evoked extracellular dopamine (DA) concentrations, suggesting that moderate loss of DA axons in the mPFC is sufficient to alter the neurochemical activity of the remaining DA neurons (Neuroscience 93:497-505, 1999).To further assess the functional consequences of partial mPFC DA depletion, we examined the effects of 6-hydroxydopamine lesions of the rat mPFC on behavior in a T-maze delayed-response task. We also assessed whether chronic administration of the norepinephrine (NE) uptake inhibitor, desipramine (DMI), attenuates lesion-induced deficits in T-maze performance. Previous research indicates that inhibition of NE transport in the mPFC results in a concomitant increase in extracellular DA and NE.Moderate loss of mPFC DA and NE (similar to 50 and 10% loss, respectively) was sufficient to impair delayed-response behavior, in part due to an increase in perseverative responding. Chronic DMI treatment (3 mg/kg delivered via osmotic pumps) impaired performance of control rats but attenuated the deficits in delayed-response behavior in rats previously sustaining loss of mPFC DA and NE (similar to 75 and 35% loss, respectively).These data suggest that moderate loss of DA and NE in the prefrontal cortex is sufficient to impair cognitive function, and these behavioral effects are attenuated by inhibition of the NE transporter.