Activation of 5-HT6 receptors facilitates attentional set shifting
Activation of 5-HT6 receptors facilitates attentional set shifting
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DOI：
10.1007/s00213-009-1701-6
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发表时间：
2010-01-01
影响因子：
3.4
通讯作者：
Sharp, Trevor
中科院分区：
文献类型：
--
作者：
Burnham, Katherine E.;Baxter, Mark G.;Sharp, Trevor
前额叶皮层（PFC）依赖的执行功能在一系列精神疾病中被破坏，并且可以使用注意定势转移范式在非人类灵长类动物和啮齿动物中建模。尽管前额叶皮层富含相关的神经递质靶点，包括5-羟色胺（5-HT），但目前很少有增强注意定势转移的药理学策略。虽然5-HT耗竭研究不支持的作用，5-HT在注意定势转移，使用特定的受体激动剂的5-HT激活的效果还没有被tested.This研究的影响，一种新的，选择性的5-HT 6受体激动剂，WAY 181187，在PFC依赖的额外维（艾德）注意定势转移的大鼠模型。与注射溶剂的对照组相比，WAY 181187促进了艾德集合移位，但没有改变任务的其他非艾德阶段（包括维度内集合移位和逆转）。这种作用被选择性5-HT 6拮抗剂SB 399885阻断，单独使用没有作用。WAY 181187增强了艾德定势转移，即使是在注意定势获得后给药，从而排除了注意定势形成的障碍。在单独的实验中，在增加艾德集移位的剂量下，WAY 181187以SB 399885敏感的方式增加了内侧PFC中的Fos样免疫反应性，表明该区域的5-HT 6受体介导的激活。由5-HT 6受体激活介导。
Prefrontal cortex (PFC)-dependent executive function is disrupted in a range of psychiatric disorders and can be modelled in non-human primates and rodents using attentional set-shifting paradigms. There are few current pharmacological strategies for enhancing attentional set shifting, although the PFC is rich in relevant neurotransmitter targets, including 5-hydroxytryptamine (5-HT). Although 5-HT depletion studies do not support a role for 5-HT in attentional set shifting, the effect of 5-HT activation using specific receptor agonists has not been tested.This study investigated the effect of a novel, selective 5-HT6 receptor agonist, WAY181187, in a rat model of PFC-dependent extra-dimensional (ED) attentional set shifting. The effect of this agent on immediate early gene expression in the medial PFC and other regions was also examined.Compared to vehicle-injected controls, WAY181187 facilitated ED set shifting but did not change other non-ED phases of the task (including intra-dimensional set shifting and reversal). This effect was blocked by the selective 5-HT6 antagonist SB399885, which alone had no effect. WAY181187 enhanced ED set shifting even when administered after the attentional set had been acquired, thereby ruling out impairments in attentional set formation. In separate experiments, at a dose that increased ED set shifting, WAY181187 increased Fos-like immunoreactivity in the medial PFC in a SB399885-sensitive manner, suggesting a 5-HT6 receptor-mediated activation of this region.Through use of a novel 5-HT agonist, these experiments reveal a previously unrecognised role for 5-HT activation in PFC-dependent executive function, mediated by 5-HT6 receptor activation.