Mulholland P J, Self R L, Harris B R, Littleton J M, Prendergast M A
Department of Psychology, University of Kentucky, 115 Kastle Hall, Lexington, KY 40506-0044, USA.
Neuroscience. 2004;125(3):671-82. doi: 10.1016/j.neuroscience.2004.02.007.
Hypercortisolemia, long-term exposure of the brain to high concentrations of stress hormones (i.e. cortisol), may occur in patients suffering from depression, alcoholism, and other disorders. This has been suggested to produce neuropathological effects, in part, via increased function or sensitivity of N-methyl-d-aspartate (NMDA)-type glutamate receptors. Given that cigarette smoking is highly prevalent in some of these patient groups and nicotine has been shown to reduce toxic consequences of NMDA receptor function, it may be suggested that nicotine intake may attenuate the neurotoxic effects of hypercortisolemia. To investigate this possibility, organotypic hippocampal slice cultures derived from rat were pre-treated with corticosterone (0.001-1 microM) alone or in combination with selective glucocorticoid receptor antagonists for 72-h prior to a brief (1-h) NMDA exposure (5 microM). Pre-treatment with corticosterone (0.001-1 microM) alone did not cause hippocampal damage, while NMDA exposure produced significant cellular damage in the cornu ammonis (CA)1 subregion. No significant damage was observed in the dentate gyrus or CA3 regions following NMDA exposure. Pre-treatment of cultures with corticosterone (0.1-1 microM) markedly exacerbated NMDA-induced CA1 and dentate gyrus region damage. This effect in the CA1 region was prevented by co-administration of the glucocorticoid receptor antagonist RU486 (>or=1 microM), but not spironolactone (1-10 microM), a mineralocorticoid receptor antagonist. In a second series of studies, both acute and pre-exposure of cultures to (-)-nicotine (1-10 microM) significantly reduced NMDA toxicity in the CA1 region. Co-administration of cultures to (-)-nicotine (1-10 microM) with 100 nM corticosterone prevented corticosterone's exacerbation of subsequent CA1 insult. This protective effect of (-)-nicotine was not altered by co-exposure of cultures to 10 microM dihydro-beta-erythroidine but was blocked by co-exposure to 100 nM methyllycaconitine, suggesting the involvement of nicotinic acetylcholine receptors possessing the alpha7* subunit. The present studies suggest a role for hypercortisolemia in sensitizing the hippocampal NMDA receptor system to pathological activation and indicate that prolonged nicotine exposure attenuates this sensitization. Thus, it is possible that one consequence of heavy smoking in those suffering from hypercortisolemia may be a reduction of neuronal injury and sparing of cellular function.
高皮质醇血症，即大脑长期暴露于高浓度应激激素（即皮质醇）下，可能发生在患有抑郁症、酗酒和其他疾病的患者身上。有人认为，这部分是通过增加 N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体的功能或敏感性而产生神经病理效应。鉴于吸烟在其中一些患者群体中非常普遍，并且已证明尼古丁可降低 NMDA 受体功能的毒性后果，因此有人认为摄入尼古丁可能会减轻高皮质醇血症的神经毒性作用。为了研究这种可能性，将源自大鼠的器官型海马切片培养物单独用皮质酮（0.001 - 1 microM）或与选择性糖皮质激素受体拮抗剂联合预处理 72 小时，然后进行短暂（1 小时）的 NMDA 暴露（5 microM）。单独用皮质酮（0.001 - 1 microM）预处理不会导致海马损伤，而 NMDA 暴露会在海马角（CA）1 亚区产生显著的细胞损伤。NMDA 暴露后，在齿状回或 CA3 区域未观察到明显损伤。用皮质酮（0.1 - 1 microM）预处理培养物会显著加剧 NMDA 诱导的 CA1 和齿状回区域损伤。在 CA1 区域的这种效应可通过同时给予糖皮质激素受体拮抗剂 RU486（≥1 microM）来预防，但不能通过给予盐皮质激素受体拮抗剂螺内酯（1 - 10 microM）来预防。在第二项研究系列中，培养物急性暴露和预先暴露于（-）-尼古丁（1 - 10 microM）均显著降低了 CA1 区域的 NMDA 毒性。将培养物同时给予（-）-尼古丁（1 - 10 microM）和 100 nM 皮质酮可预防皮质酮对随后 CA1 损伤的加剧作用。（-）-尼古丁的这种保护作用不会因培养物同时暴露于 10 microM 二氢-β-刺桐啶而改变，但会因同时暴露于 100 nM 甲基lycaconitine 而被阻断，这表明具有α7*亚基的烟碱型乙酰胆碱受体参与其中。目前的研究表明高皮质醇血症在使海马 NMDA 受体系统对病理性激活敏感化方面起作用，并表明长期尼古丁暴露可减轻这种敏感化。因此，对于患有高皮质醇血症的人来说，大量吸烟的一个后果可能是减少神经元损伤并保留细胞功能。
