Developmental Psychiatry, University of Nottingham, Nottingham, UK.
J Psychopharmacol. 2024 Jul;38(7):581-596. doi: 10.1177/02698811241261022. Epub 2024 Jul 23.
Pramipexole, a D2/D3 dopamine receptor agonist, is used to treat the motor symptoms of Parkinson's disease, caused by degeneration of the dopaminergic nigrostriatal pathway. There are three paradoxes associated with its mode of action. Firstly, stimulation of D2/D3 receptors leads to neuronal inhibition, although pramipexole does not inhibit but promotes some dopamine-modulated functions, such as locomotion and reinforcement. Secondly, another dopamine-modulated function, arousal, is not promoted but inhibited by pramipexole, leading to sedation. Thirdly, pramipexole-evoked sedation is associated with an increase in pupil diameter, although sedation is expected to cause pupil constriction. To resolve these paradoxes, the path from stimulation of D2/D3 receptors to the modification of dopamine-modulated functions has been tracked. The functions considered are modulated by midbrain dopaminergic nuclei: locomotion - substantia nigra pars compacta (SNc), reinforcement/motivation - ventral tegmental area (VTA), sympathetic activity (as reflected in pupil function) - VTA; arousal - ventral periaqueductal grey (vPAG), with contributions from VTA and SNc. The application of genetics-based molecular techniques (optogenetics and chemogenetics) has enabled tracing the chains of neurones from the dopaminergic nuclei to their final targets executing the functions. The functional neuronal circuits linked to the D2/D3 receptors in the dorsal and ventral striata, stimulated by inputs from SNc and VTA, respectively, may explain how neuronal inhibition induced by pramipexole is translated into the promotion of locomotion, reinforcement/motivation and sympathetic activity. As the vPAG may increase arousal mainly by stimulating cortical D1 dopamine receptors, pramipexole would stimulate only presynaptic D2/D3 receptors on vPAG neurones, curtailing their activity and leading to sedation.
普拉克索是一种 D2/D3 多巴胺受体激动剂，用于治疗多巴胺能黑质纹状体通路变性引起的帕金森病的运动症状。其作用机制有三个矛盾之处。首先，D2/D3 受体的刺激会导致神经元抑制，尽管普拉克索不会抑制，而是促进一些多巴胺调节的功能，如运动和强化。其次，另一个多巴胺调节的功能，觉醒，不会被普拉克索促进，而是被抑制，导致镇静。第三，普拉克索引起的镇静与瞳孔直径的增加有关，尽管镇静预计会导致瞳孔收缩。为了解决这些矛盾，人们追踪了从 D2/D3 受体刺激到多巴胺调节功能改变的途径。所考虑的功能是由中脑多巴胺能核调制的：运动 - 黑质致密部（SNc），强化/动机 - 腹侧被盖区（VTA），自主神经活动（如瞳孔功能所反映）- VTA；觉醒 - 腹侧导水管周围灰质（vPAG），来自 VTA 和 SNc 的贡献。基于遗传的分子技术（光遗传学和化学遗传学）的应用，使得能够追踪从中脑多巴胺能核到执行功能的最终靶标神经元的链。与背侧和腹侧纹状体中的 D2/D3 受体相连的功能性神经元回路，分别由 SNc 和 VTA 的输入刺激，可能解释了普拉克索诱导的神经元抑制如何转化为运动、强化/动机和自主神经活动的促进。由于 vPAG 可能主要通过刺激皮质 D1 多巴胺受体来增加觉醒，普拉克索只会刺激 vPAG 神经元上的突触前 D2/D3 受体，抑制它们的活动，导致镇静。
