Rogóz Z, Skuza G, Legutko B
Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
J Physiol Pharmacol. 2007 Jun;58(2):219-34.
The problem of drug-resistant depression indicates a strong need for alternative antidepressant therapies. In our earlier papers we described synergistic, antidepressant-like effects of a combination of imipramine (IMI) and amantadine (AMA) in the forced swimming test in rats, an animal model of depression. Moreover, preliminary clinical data showed that the above-mentioned combination had beneficial effects in treatment-resistant patients. In addition, a number of studies predicted a role of the brain-derived neurotrophic factor (BDNF) in the mechanism of action of antidepressant drugs (ADs). Since the most potent effect of ADs on BDNF gene expression was found after prolonged treatment, in the present study we investigated the influence of repeated treatment with IMI (5 or 10 mg/kg) and AMA (10 mg/kg), given separately or jointly (twice daily for 14 day), on mRNA level (the Northern blot) in the hippocampus and cerebral cortex. The experiment was carried out on male Wistar rats. The tissue for biochemical assays was dissected 24 h after the last dose of IMI and AMA. We also studied the effect of repeated treatment with IMI and AMA on the action of 5-HT(1A)- and 5-HT(2A) receptor agonists (8-OH-DPAT and (+/-)DOI, respectively) in behavioral tests. The obtained results showed that in the hippocampus IMI (10 mg/kg), and in the cerebral cortex IMI (5 and 10 mg/kg) and AMA (10 mg/kg) significantly elevated BDNF mRNA level. Joint administration of IMI (5 or 10 mg/kg) and AMA (10 mg/kg) induced a more potent increase BDNF gene expression in the hippocampus (but not in cerebral cortex) and either inhibited the behavioral syndrome induced by (+/-)DOI or did not change the action of 8-OH-DPAT (compared to treatment with either drug alone). The obtained results suggest that the enhancement of BDNF gene expression may be essential for the therapeutic effect of co-administration of IMI and AMA to drug-resistant depressed patients, and that among other mechanisms, 5-HT(2A) receptors possibly play some role in this effect.
耐药性抑郁症问题表明迫切需要替代性抗抑郁疗法。在我们早期的论文中，我们描述了丙咪嗪（IMI）和金刚烷胺（AMA）联合用药在大鼠强迫游泳试验（一种抑郁症动物模型）中具有协同、类抗抑郁作用。此外，初步临床数据表明上述联合用药对难治性患者有有益效果。另外，多项研究预测脑源性神经营养因子（BDNF）在抗抑郁药物（ADs）的作用机制中发挥作用。由于发现ADs对BDNF基因表达的最显著作用出现在长期治疗后，在本研究中，我们调查了单独或联合给予IMI（5或10mg/kg）和AMA（10mg/kg）（每日两次，共14天）重复给药对海马体和大脑皮层中mRNA水平（Northern印迹法）的影响。实验在雄性Wistar大鼠身上进行。在最后一剂IMI和AMA给药24小时后解剖用于生化分析的组织。我们还研究了IMI和AMA重复给药对行为测试中5-HT(1A)和5-HT(2A)受体激动剂（分别为8-OH-DPAT和(+/-)DOI）作用的影响。所得结果表明，在海马体中IMI（10mg/kg），在大脑皮层中IMI（5和10mg/kg）以及AMA（10mg/kg）显著提高了BDNF mRNA水平。联合给予IMI（5或10mg/kg）和AMA（10mg/kg）在海马体中诱导了更显著的BDNF基因表达增加（但在大脑皮层中未出现），并且要么抑制了(+/-)DOI诱导的行为综合征，要么未改变8-OH-DPAT的作用（与单独使用任一药物治疗相比）。所得结果表明，BDNF基因表达的增强可能是IMI和AMA联合给药对耐药性抑郁症患者治疗效果的关键，并且在其他机制中，5-HT(2A)受体可能在这种作用中发挥了一定作用。
