The 5-HT1A/1B-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity
The 5-HT1A/1B-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity
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DOI：
10.1016/j.ejphar.2016.11.024
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发表时间：
2017-01-05
影响因子：
5
通讯作者：
Guentuerkuen, Onur
中科院分区：
文献类型：
--
作者：
Korte, S. Mechiel;Prins, Jolanda;Guentuerkuen, Onur
尽管受体结合特征存在差异，但5-HT 1A/1B受体激动剂eltoprazine的行为药物特征与各种精神兴奋剂药物相似。这些精神兴奋剂在治疗冲动性障碍方面是有效的，很可能是因为它们增加了前额叶皮层中的去甲肾上腺素（NE）和多巴胺（DA）水平。然而，安非他明和哌醋甲酯也会增加中脑核（NAc）中的多巴胺水平，而NAc在动机、愉悦和奖励中起着重要作用。目前尚不清楚eltoprazine如何影响内侧前额叶皮层（mPFC）、眶额皮层（OFC）和NAc中的单胺释放。也不清楚eltoprazine是否影响不同形式的冲动和大脑奖励机制，因此，在本研究中，我们按照以下顺序研究了eltoprazine在大鼠中的作用：1）使用体内微透析的单胺能系统的活性，2）使用颅内自我刺激（ICSS）程序测量的奖励动机，以及最后，3）延迟-厌恶任务中的“等待”冲动和停止-信号任务中的“停止”冲动。微透析研究清楚地表明，eltoprazine增加了mPFC和OFC中的DA和NE释放，但仅增加了NAc中的DA浓度。相比之下，eltoprazine减少了mPFC和NAc中的5-HT释放（在OFC中未检测到）。值得注意的是，eltoprazine减少了冲动选择，但增加了冲动行为。此外，在艾托哌嗪治疗后，脑刺激的回报较低。这些结果进一步支持了长期存在的假设，即“等待”和“停止”冲动是由不同的神经回路调节的，因为5-HT 1A/1B受体激活减少了冲动选择，但增加了冲动行为。
The 5-HT1A/1B-receptor agonist eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward.How eltoprazine affects monoamine release in the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the NAc is unknown. It is also unknown whether eltoprazine affects different forms of impulsivity and brain reward mechanisms.Therefore, in the present study, we investigate the effects of eltoprazine in rats in the following sequence: 1) the activity of the monoaminergic systems using in vivo microdialysis, 2) motivation for reward measured using the intracranial self-stimulation (ICSS) procedure, and finally, 3) "waiting" impulsivity in the delay-aversion task, and the "stopping" impulsivity in the stop-signal task.The microdialysis studies clearly showed that eltoprazine increased DA and NE release in both the mPFC and OFC, but only increased DA concentration in the NAc. In contrast, eltoprazine decreased 5-HT release in the mPFC and NAc (undetectable in the OFC). Remarkably, eltoprazine decreased impulsive choice, but increased impulsive action. Furthermore, brain stimulation was less rewarding following eltoprazine treatment. These results further support the long-standing hypothesis that "waiting" and "stopping" impulsivity are regulated by distoinct neural circuits, because 5-HT1A/1B-receptor activation decreases impulsive choice, but increases impulsive action.