Effect of 5-HT2A and 5-HT2C receptors on temporal discrimination by mice.
Effect of 5-HT2A and 5-HT2C receptors on temporal discrimination by mice.
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DOI：
10.1016/j.neuropharm.2016.03.038
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发表时间：
2016-08
影响因子：
4.7
通讯作者：
Young JW
中科院分区：
文献类型：
--
作者：
Halberstadt AL;Sindhunata IS;Scheffers K;Flynn AD;Sharp RF;Geyer MA;Young JW
在精神分裂症患者中观察到时间缺陷。5-羟色胺能致幻剂也能改变对时间的主观体验。描述多巴胺能系统调节时间的机制将增加我们对5-羟色胺（5-HT）和精神分裂症之间联系的理解，并将提供对致幻剂作用机制的深入了解。我们研究了致幻剂和其他5-HT 2受体配体是否会改变小鼠的间隔时间。训练C57 BL/6 J小鼠执行离散试验时间辨别任务。在离散试验任务中，在不同的时间间隔后向小鼠提供两个杠杆。间隔< 6.5 s时，A杆反应增强;间隔> 6.5 s时，B杆反应增强。将2参数逻辑函数拟合到杠杆B的比例选择（%B响应），得到无差异点（T50）和韦伯分数（计时精度的度量）的估计值。5-HT 2A拮抗剂M100907增加T50，而5-HT 2C拮抗剂SB-242，084降低T50。结果表明，5-HT_（2A）和5-HT_（2C）受体对内起搏的速度有对抗作用。致幻剂2，5-二甲氧基-4-碘苯丙胺（DOI; 3 mg/kg IP）是一种5-HT 2激动剂，在长刺激间隔下使反应曲线变平并将其向右移动，导致T50和Weber分数增加。DOI的作用被M100907（0.03 mg/kg SC）拮抗，但不受SB-242，084（0.1 mg/kg SC）的影响。与DOI相似，选择性5-HT 2A激动剂25 CN-NBOH（6 mg/kg SC）降低了长刺激间隔下的%B反应，并增加了T50和Weber分数。这些结果表明，致幻剂改变小鼠的时间知觉，这种作用是由5-HT 2A介导的。看来，5-HT调节时间知觉，这表明改变的多巴胺能信号可能有助于在精神分裂症和其他精神疾病中观察到的时间缺陷。
Timing deficits are observed in patients with schizophrenia. Serotonergic hallucinogens can also alter the subjective experience of time. Characterizing the mechanism through which the serotonergic system regulates timing will increase our understanding of the linkage between serotonin (5-HT) and schizophrenia, and will provide insight into the mechanism of action of hallucinogens. We investigated whether interval timing in mice is altered by hallucinogens and other 5-HT2 receptor ligands. C57BL/6J mice were trained to perform a discrete-trials temporal discrimination task. In the discrete-trials task, mice were presented with two levers after a variable interval. Responding on lever A was reinforced if the interval was < 6.5 s, and responding on lever B was reinforced if the interval was > 6.5 s. A 2-parameter logistic function was fitted to the proportional choice for lever B (%B responding), yielding estimates of the indifference point (T50) and the Weber fraction (a measure of timing precision). The 5-HT2A antagonist M100907 increased T50, whereas the 5-HT2C antagonist SB-242,084 reduced T50. The results indicate that 5-HT2A and 5-HT2C receptors have countervailing effects on the speed of the internal pacemaker. The hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI; 3 mg/kg IP), a 5-HT2 agonist, flattened the response curve at long stimulus intervals and shifted it to the right, causing both T50 and the Weber fraction to increase. The effect of DOI was antagonized by M100907 (0.03 mg/kg SC) but was unaffected by SB-242,084 (0.1 mg/kg SC). Similar to DOI, the selective 5-HT2A agonist 25CN-NBOH (6 mg/kg SC) reduced %B responding at long stimulus intervals, and increased T50 and the Weber fraction. These results demonstrate that hallucinogens alter temporal perception in mice, effects that are mediated by the 5-HT2A. It appears that 5-HT regulates temporal perception, suggesting that altered serotonergic signaling may contribute to the timing deficits observed in schizophrenia and other psychiatric disorders.