Noradrenaline reuptake inhibition increases control of impulsive action by activating D1-like receptors in the infralimbic cortex
Noradrenaline reuptake inhibition increases control of impulsive action by activating D1-like receptors in the infralimbic cortex
复制标题
DOI：
10.1016/j.ejphar.2018.11.041
复制
发表时间：
2019-02-05
影响因子：
5
通讯作者：
Yoshioka, Mitsuhiro
中科院分区：
文献类型：
--
作者：
Sasamori, Hitomi;Ohmura, Yu;Yoshioka, Mitsuhiro
更高的冲动是犯罪、药物滥用和自杀的危险因素。然而，临床上只有少数药物可用于治疗冲动控制缺陷。我们最近提出了一种策略，通过调查临床上可用的药物，增加细胞外多巴胺水平在内侧前额叶皮层和刺激多巴胺D-1样受体，而不增加细胞外多巴胺水平在腹侧纹状体，以确定潜在的药物来治疗这些疾病。为了确定这种策略是否有前途，我们使用3选择系列反应时间任务，研究了度洛沙汀（一种可能符合这些标准的去甲肾上腺素再摄取抑制剂）对成年雄性Wistar/ST大鼠冲动行为的影响。由于去甲肾上腺素转运蛋白在某些脑区转运多巴胺，因此使用体内微透析评价了度洛沙汀对内侧前额叶皮质和腹侧纹状体的一部分丘脑核细胞外多巴胺水平的影响。我们的研究结果表明，度洛沙汀的管理减少冲动行为和增加细胞外多巴胺水平的mPFC，但不是在延髓核。将选择性D-1样受体拮抗剂微量注射到边缘下皮层，阻断了度洛沙汀对冲动行为的抑制。此外，我们证明了微量注射也阻断了托莫西汀对冲动行为的抑制，托莫西汀是一种去甲肾上腺素再摄取抑制剂，也是一种已确定的抗冲动药物。这些结果支持我们提出的识别和开发抗冲动药物的策略。
Higher impulsivity is a risk factor for criminal involvement, substance abuse, and suicide. However, only a few drugs are clinically available for the treatment of deficient impulse control. We recently proposed a strategy for identifying potential drugs to treat such disorders by investigating clinically available drugs that increase extracellular dopamine levels in the medial prefrontal cortex and stimulate dopamine D-1-like receptors without increasing extracellular dopamine levels in the ventral striatum. To determine whether this strategy is promising, we examined the effects of duloxetine, a serotonin-noradrenaline reuptake inhibitor that might meet these criteria, on impulsive action in adult male Wistar/ST rats using a 3-choice serial reaction time task. The effects of duloxetine on extracellular dopamine levels in the medial prefrontal cortex and nucleus accumbens, a part of the ventral striatum were evaluated using in vivo microdialysis, as the noradrenaline transporter transports dopamine in some brain regions. Our results showed that the administration of duloxetine reduced impulsive actions and increased extracellular dopamine levels in the mPFC but not in the nucleus accumbens. Microinjection of a selective D-1-like receptor antagonist into the infralimbic cortex blocked the suppression of impulsive action by duloxetine. In addition, we demonstrated that the microinjection also blocked the suppression of impulsive action by atomoxetine, a noradrenaline reuptake inhibitor and an established anti-impulsive drug. These results support our proposed strategy for identifying and developing anti-impulsivity drugs.