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A novel action of antidepressants : effects on monoaminergic fiber regeneration

抗抑郁药的新作用：对单胺能纤维再生的影响

基本信息

批准号：
03807070
负责人：
NAKAMURA Shoji
金额：
$ 1.15万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

This research has been performed to extend our previous work, in which the antidepressants desipramine (DMI) and maprotiline (MPL) were shown to induce axonal regeneration of noradrenergic neurons in the rat cerebral cortex. The antidepressants DMI and MPL are known to block the reuptake of noradrenaline (NA), while there are other antidepressants that reveal weak or no potency for NA reuptake blockade. First, to see if antidepressants other than DMI and MPL induce the regeneration of noradrenergic axons, I examined mianserin (MIA) and fluoxetine (FLU). MIA has little or no effect on NA reuptake blockade but may enhance NA release by blockade of presynaptic alpha2-adrenoceptors. FLU is a potent reuptake blocker of serotonin but not of NA. It was found that MIA induced regeneration of cortical noradrenergic axons whereas FLU was ineffective. These findings suggest that the antidepressant-induced regeneration of noradrenergic axons is associated, at least in part, with enhanced noradrenergic transmission.To see if beta-adrenoceptors are involved in the antidepressant-induced regeneration of noradrenergic axons, the effects of the beta-adrenoceptor blocker propranolol (PRP) was examined. First, the symmetrical sites of the cerebral cortex in the two hemispheres were pretreated with 6-hydroxydopamine (6-OHDA). Two weeks after 6-OHDA pretreatment, the same cortical site of one hemisphere was infused with DMI by means of osmotic minipumps, while the corresponding site of the other hemisphere was infused with DMI (1 mM) + PRP (1 mM). After more than two weeks from start of the infusion, the brain was processed for the immunohistochemistry using an antibody to dopamine-beta-hydroxylase. It was found that PRP attenuated the effects of the DMI-induced regeneration of noradrenergic axons. This finding suggests that beta-adrenoceptors are involved, at least in part, in the antidepressant-induced regeneration of noradrenergic axons.

本研究是对我们以前的工作的扩展，其中抗抑郁药地昔帕明（desipramine，DSI）和马普替林（maprotiline，MPL）被证明能诱导大鼠大脑皮层去甲肾上腺素能神经元的轴突再生。已知抗抑郁药PGEX和MPL阻断去甲肾上腺素（NA）的再摄取，而其他抗抑郁药对NA再摄取阻断的效力较弱或没有效力。首先，为了观察除多巴胺和MPL以外的抗抑郁药是否能诱导去甲肾上腺素能轴突的再生，我检测了米安色林（MIA）和氟西汀（FLU）。MIA对NA再摄取阻断作用很小或没有作用，但可能通过阻断突触前α 2-肾上腺素受体而增强NA释放。FLU是5-羟色胺而不是NA的有效再摄取阻滞剂。结果发现，MIA诱导皮质去甲肾上腺素能轴突再生，而FLU是无效的。这些发现表明，抗抑郁药诱导的去甲肾上腺素能轴突再生与增强的去甲肾上腺素能transmission.To了解β-肾上腺素受体是否参与抗抑郁药诱导的去甲肾上腺素能轴突再生，β-肾上腺素受体阻滞剂普萘洛尔（PRP）的影响进行了检查。首先，用6-羟基多巴胺（6-OHDA）预处理两半球大脑皮质的对称部位。6-OHDA预处理后两周，通过渗透微泵向一侧半球的相同皮质部位输注Na 2CO 3，而另一侧半球的相应部位输注Na 2CO 3（1 mM）+ PRP（1 mM）。输注开始后超过两周后，使用多巴胺-β-羟化酶抗体处理脑进行免疫组织化学。结果发现，PRP衰减去甲肾上腺素能轴突的DMI诱导的再生的影响。这一发现表明，β-肾上腺素能受体参与，至少部分，在抗抑郁药诱导的再生去甲肾上腺素能轴突。