新型 5-HT6 拮抗剂 PRX-07034 对大鼠认知灵活性和工作记忆的影响。
The effects of PRX-07034, a novel 5-HT6 antagonist, on cognitive flexibility and working memory in rats.
机构信息
Department of Psychology, University of Illinois at Chicago, 1007 West Harrison Street, Chicago, IL 60607, USA.
出版信息
Psychopharmacology (Berl). 2012 Apr;220(4):687-96. doi: 10.1007/s00213-011-2518-7. Epub 2011 Oct 12.
RATIONALE
Accumulating evidence indicates that schizophrenia and autism spectrum disorder patients are marked by cognitive deficits in working memory and strategy switching. There is accumulating evidence that 5-hydroxytryptamine (5-HT)(6) receptors may serve as a useful target to improve cognitive functioning.
OBJECTIVES
In the present experiments, the novel 5-HT(6) antagonist, PRX-07034, was examined for its selectivity of the 5-HT(6) receptor, as well as its effect on delayed spontaneous alternation and strategy switching.
METHODS
The binding affinity of PRX-07034 to the 5-HT(6) receptor, other 5-HT receptors, as well as other G-protein coupled receptors, ion channels, and transporters was evaluated. Cyclic AMP production was measured from transfected HEK-293 cells. In separate behavioral experiments, rats received different doses of PRX-07034 (0.1, 1, or 3 mg/kg, i.p.) 30 min prior to delayed spontaneous alternation testing or prior to the acquisition and switch phases in a place-response switch test.
RESULTS
The results indicated that PRX-07034 is both a potent (Ki = 4-8 nM) and highly selective 5-HT(6) receptor antagonist (≥100-fold selectivity for the 5-HT(6) receptor compared to 68 other GPCRs, ion channels, and transporters, except D(3) (Ki = 71 nM) and 5-HT(1B) (Ki = 260 nM) receptors. For cyclic AMP quantification, PRX-07034 demonstrated antagonist activity (IC(50) = 19 nM) without an effect on basal levels and did not show any agonist activity up to 10 μM. PRX-07034 at 1 and 3 mg/kg (but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation. The drug at 1 and 3 mg/kg also enhanced switching between a place and response strategy, but did not affect initial learning of either a place or response discrimination.
CONCLUSIONS
These findings demonstrate that PRX-07034 is a selective 5-HT(6) receptor antagonist that may represent a novel treatment for enhancing working memory and cognitive flexibility.
背景
越来越多的证据表明，精神分裂症和自闭症谱系障碍患者的工作记忆和策略转换方面存在认知缺陷。越来越多的证据表明，5-羟色胺（5-HT）（6）受体可能是改善认知功能的有用靶点。
目的
在本实验中，新型 5-HT（6）拮抗剂 PRX-07034 的 5-HT（6）受体选择性以及对延迟自发交替和策略转换的影响进行了研究。
方法
评估了 PRX-07034 与 5-HT（6）受体、其他 5-HT 受体以及其他 G 蛋白偶联受体、离子通道和转运体的结合亲和力。通过转染的 HEK-293 细胞测量环磷酸腺苷的产生。在单独的行为实验中，大鼠在延迟自发交替测试前 30 分钟或在位置反应转换测试的获取和转换阶段前接受不同剂量的 PRX-07034（0.1、1 或 3 mg/kg，ip）。
结果
结果表明，PRX-07034 是一种强效（Ki=4-8 nM）且高度选择性的 5-HT（6）受体拮抗剂（与 68 种其他 GPCR、离子通道和转运体相比，对 5-HT（6）受体的选择性> 100 倍，除 D（3）（Ki=71 nM）和 5-HT（1B）（Ki=260 nM）受体）。对于环磷酸腺苷的定量，PRX-07034 表现出拮抗剂活性（IC50=19 nM），而对基础水平没有影响，并且在高达 10 μM 时没有表现出任何激动剂活性。PRX-07034 1 和 3 mg/kg（但不是 0.1 mg/kg）显著增强了延迟自发交替。该药物在 1 和 3 mg/kg 时还增强了位置和反应策略之间的转换，但不影响位置或反应辨别能力的初始学习。
结论
这些发现表明，PRX-07034 是一种选择性 5-HT（6）受体拮抗剂，可能代表一种治疗增强工作记忆和认知灵活性的新方法。
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