Chaurasia C S, Chen C E, Rubin J, Dewey S L
College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, NY 11439, USA.
J Pharm Pharmacol. 1998 Dec;50(12):1377-85. doi: 10.1111/j.2042-7158.1998.tb03363.x.
Recent studies indicating interaction of oestrogens with central cholinergic, dopaminergic and 5-HTergic systems have led to the assumption of a protective role of oestrogens in certain neurodegenerative disorders. The non-steroidal drug tamoxifen, a mixed oestrogen agonist-antagonist, has been shown to modulate central nervous system functions in the corpus striatum. In this study we used a microdialysis technique to examine the effects of tamoxifen upon the striatal dopaminergic and 5-HTergic systems in intact freely moving male rats. The extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid were measured after intraperitoneal administration of either the control or tamoxifen, and were compared with their corresponding baseline levels. Significant 25-35% increases in the baseline levels of dopamine and 3,4-dihydroxyphenylacetic acid were observed after the highest doses of tamoxifen (1.5 mg kg(-1) and 30 mg kg(-1), respectively), whereas the lowest dose of tamoxifen (0.3 mg kg(-1)) elevated dopamine and 3,4-dihydroxyphenylacetic acid levels by a detectable 15% of the basal. In addition, the ratio of 3,4-dihydroxyphenylacetic acid-to-dopamine remained unchanged in comparison with that of the pretreatment levels. Whereas no change in the striatal 5-hydroxyindoleacetic acid concentrations was seen with the lowest and highest dose regimen, the intermediate dose elicited a moderate increase (20%) in basal 5-hydroxyindoleacetic acid levels. The pharmacological relevance of the effects of tamoxifen on the dopaminergic and 5-HTergic systems, as a prelude to the development of non-steroidal oestrogenic compounds in reducing the risk of neurodegenerative disorders such as Alzheimer's disease, is discussed.
近期研究表明雌激素与中枢胆碱能、多巴胺能和5-羟色胺能系统存在相互作用，这使得人们推测雌激素在某些神经退行性疾病中具有保护作用。非甾体药物他莫昔芬是一种雌激素混合激动剂-拮抗剂，已被证明可调节纹状体中的中枢神经系统功能。在本研究中，我们使用微透析技术来检测他莫昔芬对完整自由活动雄性大鼠纹状体多巴胺能和5-羟色胺能系统的影响。在腹腔注射对照剂或他莫昔芬后，测量多巴胺、3,4-二羟基苯乙酸、高香草酸和5-羟吲哚乙酸的细胞外水平，并将其与相应的基线水平进行比较。在给予最高剂量的他莫昔芬（分别为1.5 mg kg⁻¹和30 mg kg⁻¹）后，观察到多巴胺和3,4-二羟基苯乙酸的基线水平显著升高25 - 35%，而最低剂量的他莫昔芬（0.3 mg kg⁻¹）使多巴胺和3,4-二羟基苯乙酸水平升高至可检测到的基础水平的15%。此外，与预处理水平相比，3,4-二羟基苯乙酸与多巴胺的比率保持不变。虽然在最低和最高剂量方案下纹状体5-羟吲哚乙酸浓度没有变化，但中间剂量使基础5-羟吲哚乙酸水平适度升高（20%）。本文讨论了他莫昔芬对多巴胺能和5-羟色胺能系统影响的药理学相关性，作为开发非甾体雌激素化合物以降低如阿尔茨海默病等神经退行性疾病风险的前奏。
