Isherwood Sarah N, Robbins Trevor W, Nicholson Janet R, Dalley Jeffrey W, Pekcec Anton
Boehringer Ingelheim Pharma GmbH & Co. KG, Div. Research Germany, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK; Department of Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK.
Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK; Department of Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK.
Neuropharmacology. 2017 Sep 1;123:249-260. doi: 10.1016/j.neuropharm.2017.05.006. Epub 2017 May 6.
Metabotropic glutamate receptor 4 (mGluR4) and dopamine D receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D receptor antagonist eticlopride, on two distinct forms of impulsivity.
Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity.
Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity.
These findings demonstrate that mGluR4s, in conjunction with D receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes.
代谢型谷氨酸受体4（mGluR4）和多巴胺D受体在纹状体-苍白球-丘脑底通路的间接通路神经元中特异性表达。这种独特的表达模式表明，mGluR4和D受体可能在行为的调节和抑制控制中发挥协同作用。我们通过测试一种功能特性明确的mGluR4正向变构调节剂4-((E)-苯乙烯基)-嘧啶-2-胺（化合物11）单独以及与D受体拮抗剂依替必利联合使用对两种不同形式冲动性的影响，来研究这种可能性。
对大鼠进行持续视觉注意力的五选择连续反应时任务（5-CSRTT）训练，并根据运动冲动性的低、中、高程度（分别为LI、MI和HI）进行分组，未筛选的大鼠作为额外的对照组。另一组大鼠进行延迟折扣任务（DDT）训练以评估选择冲动性。
对所有测试组，全身给予化合物11均剂量依赖性地增加运动冲动性并损害5-CSRTT的注意力准确性。依替必利在单独给药时对行为表现无显著影响的剂量下，选择性地减弱了化合物11诱导的冲动性增加，但未减弱伴随的注意力损害。化合物11还降低了DDT上的选择冲动性（即增加了对大的、延迟奖励的偏好）并降低了运动活性。
这些发现表明，mGluR4与D受体共同影响基于运动和选择的冲动性测量指标，因此可能是调节与多种神经精神综合征相关的冲动行为的新靶点。
