Departamento de Farmacologia, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, Porto Alegre, RS, Brazil.
Neurochem Int. 2012 Dec;61(7):1144-50. doi: 10.1016/j.neuint.2012.08.006. Epub 2012 Aug 25.
A dysfunctional glutamatergic system is thought to be central to the negative symptoms and cognitive deficits recognized as determinant to the poor quality of life of people with schizophrenia. Modulating glutamate uptake has, thus, been suggested as a novel target for antipsychotics. Alstonine is an indole alkaloid sharing with atypical antipsychotics the profile in animal models relevant to schizophrenia, though divergent in its mechanism of action. The aim of this study was to evaluate the effects of alstonine on glutamate uptake. Additionally, the effects on glutathione content and extracellular S100B levels were assessed. Acute hippocampal slices were incubated with haloperidol (10μM), clozapine (10 and 100μM) or alstonine (1-100μM), alone or in combination with apomorphine (100μM), and 5-HT(2) receptor antagonists (0.01μM altanserin and 0.1μM SB 242084). A reduction in glutamate uptake was observed with alstonine and clozapine, but not haloperidol. Apomorphine abolished the effect of clozapine, whereas 5-HT(2A) and 5-HT(2C) antagonists abolished the effects of alstonine. Increased levels of glutathione were observed only with alstonine, also the only compound that failed to decrease the release of S100B. This study shows that alstonine decreases glutamate uptake, which may be beneficial to the glutamatergic deficit observed in schizophrenia. Noteworthily, the decrease in glutamate uptake is compatible with the reversal of MK-801-induced social interaction and working memory deficits. An additional potential benefit of alstonine as an antipsychotic is its ability to increase glutathione, a key cellular antioxidant reported to be decreased in the brain of patients with schizophrenia. Adding to the characterization of the novel mechanism of action of alstonine, the lack of effect of apomorphine in alstonine-induced changes in glutamate uptake reinforces that D(2) receptors are not primarily implicated. Though clearly mediated by 5-HT(2A) and 5-HT(2C) serotonin receptors, the precise mechanisms that result in the effects of alstonine on glutamate uptake warrant elucidation.
谷氨酸能系统功能障碍被认为是精神分裂症患者生活质量差的主要原因，其特征为阴性症状和认知缺陷。因此，调节谷氨酸摄取被认为是新型抗精神病药物的靶点。阿朴吗啡是一种吲哚生物碱，与非典型抗精神病药物在与精神分裂症相关的动物模型中具有相似的特征，但作用机制不同。本研究旨在评估阿朴吗啡对谷氨酸摄取的影响。此外，还评估了对谷胱甘肽含量和细胞外 S100B 水平的影响。急性海马切片与氟哌啶醇（10μM）、氯氮平（10 和 100μM）或阿朴吗啡（1-100μM）单独或与阿朴吗啡（100μM）和 5-HT2 受体拮抗剂（0.01μM 阿仑替林和 0.1μM SB 242084）联合孵育。阿朴吗啡可消除氯氮平的作用，而 5-HT2A 和 5-HT2C 拮抗剂可消除阿朴吗啡的作用。只有阿朴吗啡可增加谷胱甘肽水平，也是唯一一种不能降低 S100B 释放的化合物。本研究表明，阿朴吗啡可减少谷氨酸摄取，这可能有益于改善精神分裂症中观察到的谷氨酸能缺陷。值得注意的是，阿朴吗啡可降低谷氨酸摄取，这与逆转 MK-801 诱导的社会互动和工作记忆缺陷兼容。阿朴吗啡作为一种抗精神病药物的另一个潜在益处是其增加谷胱甘肽的能力，谷胱甘肽是一种关键的细胞抗氧化剂，据报道，其在精神分裂症患者的大脑中减少。增加对阿朴吗啡新型作用机制的特征描述，阿朴吗啡对阿朴吗啡诱导的谷氨酸摄取变化无影响，这进一步证实 D2 受体并非主要涉及。尽管 5-HT2A 和 5-HT2C 血清素受体明显介导，但导致阿朴吗啡对谷氨酸摄取影响的确切机制仍有待阐明。
