普拉克索,D2/D3多巴胺受体激动剂,用于治疗帕金森病的运动症状,由多巴胺能黑质纹状体途径的变性引起。它的作用方式有三个悖论。首先,D2/D3受体的刺激导致神经元抑制,虽然普拉克索不抑制但促进一些多巴胺调节功能,如运动和加固。其次,另一个多巴胺调节功能,唤醒,普拉克索不促进但抑制,导致镇静。第三,普拉克索诱发的镇静作用与瞳孔直径的增加有关,虽然镇静预计会引起瞳孔收缩。为了解决这些悖论,从D2/D3受体的刺激到多巴胺调节功能的改变的路径已经被追踪.所考虑的功能由中脑多巴胺能细胞核调节:运动-黑质致密部(SNc),强化/激励-腹侧被盖区(VTA),交感神经活动(反映在瞳孔功能中)-VTA;唤醒-腹侧导水管周围灰色(vPAG),VTA和SNc的贡献。基于遗传学的分子技术(光遗传学和化学遗传学)的应用使从多巴胺能核中追踪神经元的链到执行功能的最终目标。与背侧和腹侧纹状体的D2/D3受体相连的功能性神经元回路,由SNc和VTA的输入刺激,分别,可能解释了普拉克索诱导的神经元抑制如何转化为运动的促进,强化/动机和交感神经活动。由于vPAG可能主要通过刺激皮质D1多巴胺受体来增加唤醒,普拉克索仅刺激vPAG神经元上的突触前D2/D3受体,减少他们的活动并导致镇静。
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.