Hirano Kazufumi, Piers Thomas M, Searle Kirsten L, Miller Neil D, Rutter A Richard, Chapman Paul F
Cognition & Neurodegeneration Centre, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, #03-01/02, The Helios, 11 Biopolis Way, Singapore.
Life Sci. 2009 Apr 10;84(15-16):558-62. doi: 10.1016/j.lfs.2009.01.019. Epub 2009 Feb 7.
5-HT(6) receptor subtype is predominantly expressed in the brain, and preclinical evidence suggests its potential role in the cognitive function. Brain microdialysis studies demonstrated that 5-HT(6) antagonists enhance not only cholinergic but also monoaminergic neurotransmission, a property that may differentiate from acetylcholine esterase (AChE) inhibitors such as donepezil. In this study we compared the antidepressant-like effects of 5-HT(6) antagonists with donepezil to determine whether their different effects on monoamines are behaviorally relevant.
Selective 5-HT(6) antagonists (SB-399885 and SB-271046) and donepezil were evaluated in the rat forced swimming test since this is known to identify drugs such as antidepressants which can increase brain monoamine levels. Binding assay was undertaken by using [(125)I]SB-258585 to measure brain 5-HT(6) receptor occupancy.
Systemic administration of SB-399885 (3 and 10 mg/kg, i.p.) and SB-271046 (10 and 30 mg/kg, i.p.) produced a significant reduction of immobility time in the rat forced swimming test with a similar profile in terms of 5-HT(6) receptor occupancy (62 and 96% for 3 and 10 mg/kg SB-399885 respectively; 56 and 84% for 10 and 30 mg/kg SB-271046 respectively). In contrast, donepezil (0.5 and 1 mg/kg i.p.) did not show any effects in this model.
These data suggest that 5-HT(6) antagonists, at doses corresponding to those occupy central 5-HT(6) receptors, could have an antidepressive effect in humans. This may differentiate 5-HT(6) antagonists from AChE inhibitors with respect to the mood control in the symptomatic treatment of Alzheimer's disease.
5-羟色胺（6）受体亚型主要在大脑中表达，临床前证据表明其在认知功能中具有潜在作用。脑微透析研究表明，5-羟色胺（6）拮抗剂不仅能增强胆碱能神经传递，还能增强单胺能神经传递，这一特性可能与多奈哌齐等乙酰胆碱酯酶（AChE）抑制剂不同。在本研究中，我们比较了5-羟色胺（6）拮抗剂与多奈哌齐的抗抑郁样作用，以确定它们对单胺类物质的不同作用是否与行为相关。
在大鼠强迫游泳试验中评估选择性5-羟色胺（6）拮抗剂（SB-399885和SB-271046）和多奈哌齐，因为已知该试验可识别能增加脑单胺水平的药物，如抗抑郁药。通过使用[（125）I]SB-258585进行结合试验来测量脑5-羟色胺（6）受体占有率。
腹腔注射SB-399885（3和10mg/kg）和SB-271046（10和30mg/kg）可显著减少大鼠强迫游泳试验中的不动时间，就5-羟色胺（6）受体占有率而言具有相似的特征（3和10mg/kg SB-399885分别为62%和96%；10和30mg/kg SB-271046分别为56%和84%）。相比之下，腹腔注射多奈哌齐（0.5和1mg/kg）在该模型中未显示任何作用。
这些数据表明，在占据中枢5-羟色胺（6）受体的剂量下，5-羟色胺（6）拮抗剂可能对人类具有抗抑郁作用。在阿尔茨海默病的症状治疗中，这可能使5-羟色胺（6）拮抗剂在情绪控制方面与AChE抑制剂有所不同。
